Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors

ABSTRACT

The present disclosure describes bicyclic aromatic carboxamide derivatives, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of and claims priority toU.S. patent application Ser. No. 14/797,765, filed on Jul. 13, 2015,which claims priority to U.S. Provisional Patent Application Ser. No.62/024,333, filed on Jul. 14, 2014. Each application is incorporatedherein by reference in its entirety.

TECHNICAL FIELD

The present application is concerned with pharmaceutically usefulcompounds. The disclosure provides new compounds as well as theircompositions and methods of use. The compounds inhibit the activity ofPim kinases and are therefore useful in the treatment of diseasesrelated to the activity of Pim kinases including, e.g., cancers andother diseases.

BACKGROUND

Protein kinases regulate diverse biological processes including cellgrowth, survival, differentiation, organ formation, morphogenesis,neovascularization, tissue repair, and regeneration, among others.Protein kinases also play specialized roles in a host of human diseasesincluding cancer. The three members of the Pim kinase family, oneexample of a protein kinase family, were initially identified aspreferential integration sites of Moloney leukemia virus in mouse modelsof cancer. Although possessing modest but measurable oncogenic activityalone, they potentiate pro-proliferative and pro-survival oncogenes,e.g., causing a dramatic acceleration of lymphomagenesis inMyc-transgenic or Bcl2-transgenic mice. Mikkers et al., Nature Genet.,2002, 32, 153-159; Shinto et al., Oncogene, 1995, 11, 1729-35.

The three non-receptor serine/threonine kinases Pim1, Pim2 and Pim3regulate cell proliferation and survival by impacting gene transcriptionand protein translation. Zippo, et al., Nature Cell Biol., 2007, 9,932-44; Schatz, et al., J Exp. Med., 2011, 208, 1799-1807. As opposed tonumerous other protein kinases which require activation byphosphorylation, the Pim kinases are constitutively activated and familymembers have overlapping substrate targets and biological functions,with differences between family members dictated, in part, by theirvaried tissue distribution. Expression of the Pim kinases is induced bycytokines and growth factors. Among the cytokines activating Pim kinaseexpression are cytokines which signal through the JAK/STAT pathway. Pimkinases act in parallel to the PI3K/AKT pathway, and they share severalphosphorylation targets (e.g., pBAD, p4EBP1). Inhibitors of Pim kinasesmay therefore potentiate regimens including inhibitors of either the JAKpathway or the PI3K/AKT pathway.

Overexpression of Pim kinases is detected in a wide variety ofhematologic and solid cancers. Overexpression of various family membershave been noted in multiple myeloma, A ML, pancreatic and hepatocellularcancers. Claudio et al., Blood, 2002, 100, 2175-86; Amson et al., Proc.Nat. Acad. Sci., USA, 1989, 86, 8857-61; Mizuki et al., Blood, 2003,101, 3164-73; Li et al., Canc. Res., 2006, 66, 6741-7; Fujii et al.,Int. J. Canc., 2005, 114, 209-18. Pim1 overexpression is associated withpoor prognosis in mantle cell lymphoma, esophageal and head and neckcancers. Hsi et al., Leuk. Lymph., 2008, 49, 2081-90; Liu et al., J.Surg. Oncol., 2010, 102, 683-88; Peltola et al., Neoplasia, 2009, 11,629-36. Pim2 overexpression is associated with an aggressive clinicalcourse in a subset of DLBCL patients. Gomez-Abad et al., Blood, 2011,118, 5517-27. Overexpression is often seen where Myc is overexpressedand Pim kinases can convey resistance to traditional chemotherapeuticagents and radiation. Chen et al., Blood, 2009, 114, 4150-57; Isaac etal., Drug Resis. Updates, 2011, 14, 203-11; Hsu et al., Cancer Lett.,2012, 319, 214; Peltola et al., Neoplasia, 2009, 11, 629-36.

As such, these data indicate that inhibition of Pim kinases will beuseful to provide therapeutic benefit in cancer patients.

Data from mice deficient for one or multiple Pim kinase family memberssuggests that pan-Pim inhibitor would have a favorable toxicity profile.Triple knockout mice are viable, but are slightly smaller than theirwild type littermates. Mikkers et al., Mol. Cell. Biol., 2004, 24.6104-15. Since Pim kinases are also involved in a variety of immunologicand inflammatory responses and these indications require drug agentswith fewer side effects, Pim kinase inhibitors are expected to be usefulin treating patients with colitis (Shen et al., Dig. Dis. Sci., 2012,57, 1822-31), peanut allergy (Wang et al., J. All. Clin. Immunol., 2012,130, 932-44), multiple sclerosis and lupus (Davis et al., “SmallMolecule Dual Antagonist of Pim 1 and 3 Kinases Ameliorate ExperimentalAutoimmune Encephalomyelitis”, 26^(th) Congress of the EuropeanCommittee for Treatment and Research in Multiple Sclerosis, 13-16 Oct.2010, Gothenburg, Sweden, Poster P436; Robinson et al., J. Immunol.,2012, 188, 119.9) and rheumatoid arthritis (Yang et al., Immunol. 2010,131, 174-182) and other immunological and inflammatory disorders.

The Pim kinases have therefore been identified as useful targets fordrug development efforts. Swords et al., Curr. Drug Targets, 2011,12(14), 2059-66; Merkel et al., Exp. Opin. Investig. Drugs, 2012, 21,425-38; Morwick et al., Exp. Opin. Ther. Patents, 2010, 20(2), 193-212.

Accordingly, there is a need for new compounds that inhibit Pim kinases.The present application describes new inhibitors of Pim kinases that areuseful for treating diseases associated with the expression or activityof one or more Pim kinases, e.g., cancer and other diseases.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein the variables areas defined below.

The present disclosure also provides a composition comprising a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable carrier.

The present disclosure also provides methods of treating cancer andother diseases comprising administering to a patient a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION

For the terms “e.g.” and “such as,” and grammatical equivalents thereof,the phrase “and without limitation” is understood to follow unlessexplicitly stated otherwise.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “about” means “approximately” (e.g., plus orminus approximately 10% of the indicated value).

I. Compounds

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

R¹ is H or OH;

R² is C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₃₋₇ cycloalkyl;

A is N or CH; and

R³ is H, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, Cy, -L-Cy, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1) or S(O)₂NR^(c1)R^(d1),

wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl forming R³ areeach independently unsubstituted or substituted with 1, 2 or 3substituents independently selected from halogen, C₁₋₃ haloalkyl, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1) andS(O)₂NR^(c1)R^(d1);

Cy is unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted 5-10 membered heteroaryl, unsubstituted or substituted C₃₋₆cycloalkyl or unsubstituted or substituted 4-11 memberedheterocycloalkyl,

wherein the substituted C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₆cycloalkyl or 4-11 membered heterocycloalkyl forming Cy is substitutedwith 1, 2, 3, 4 or 5 substituents each independently selected fromhalogen, R^(Cy1), R^(Cy2), C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1) andS(O)₂NR^(c1)R^(d1),

wherein each R^(Cy1) is, independently, C₁₋₆ alkyl, each of which isindependently unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from halogen, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1)NR^(c1)S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); or

wherein each R^(Cy2) is, independently, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl,5-10 membered heteroaryl, or 4-7 membered heterocycloalkyl, each ofwhich is independently unsubstituted or substituted with 1, 2 or 3substituents independently selected from halogen, C₁₋₆ alkyl, CN,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1) NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1) NR^(c1)S(O)₂R^(b1) andS(O)₂NR^(c1)R^(d1);

L is unsubstituted C₁₋₆ alkylene or C₁₋₆ alkylene substituted with 1, 2or 3 substituents independently selected from F, Cl, CN, OH, O(C₁₋₆alkyl), NH₂, NH(C₁₋₆ alkyl) and N(C₁₋₆ alkyl)₂;

R^(a1), R^(b1), R^(c1) and R^(d1), at each occurrence, are independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₃ alkyl, 5-10 membered heteroaryl-C₁₋₃alkyl, C₃₋₇ cycloalkyl-C₁₋₃ alkyl and 4-10 memberedheterocycloalkyl-C₁₋₃ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10membered heterocycloalkyl groups forming R^(a1), R^(b1), R^(c1) andR^(d1) are each optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from C₁₋₆ alkyl, R^(Cy3), halo, CN, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) and S(O)₂NR^(c2)R^(d2);

or R^(c1) and R^(d1) attached to the same N atom, together with the Natom to which they are both attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or 5-membered heteroaryl group, each optionallysubstituted with 1, 2 or 3 substituents independently selected from C₁₋₆alkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2);

wherein each R^(Cy3) is, independently, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, or 4-7 membered heterocycloalkyl, each of which isindependently unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from halogen, C₁₋₆ alkyl, CN, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2) NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2); and

R^(a2), R^(b2), R^(c2) and R^(d2) are each independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl formingR^(a2), R^(b2), R^(c2) and R^(d2) are each optionally substituted with1, 2 or 3 substituents independently selected from OH, CN, amino,NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl and C₁₋₆ haloalkoxy.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be a compound according to Formula (II):

In some embodiments, X is N.

In some embodiments, X is CH.

In some embodiments, R¹ is OH.

In some embodiments, R¹ is H.

In some embodiments, R² is C₁₋₆ alkyl.

In some embodiments, R² is C₁₋₃ alkyl.

In some embodiments, R² is methyl.

In some embodiments, R² is C₁₋₃ haloalkyl, e.g., CF₃.

In some embodiments, R² is C₃₋₇ cycloalkyl.

In some embodiments, R² is cyclopropyl.

In some embodiments, A is N.

In some embodiments, A is CH.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is of any one of the following Formulae (III)to (VIII):

In some embodiments, R³ is C₁₋₆ alkyl, Cy or -L-Cy, wherein the C₁₋₆alkyl forming R³ is unsubstituted or substituted with 1, 2 or 3substituents independently selected from halogen, C₁₋₃ haloalkyl, CN,and OR^(a1).

In some embodiments, R³ is C₁₋₆ alkyl, Cy, or -L-Cy, wherein Cy isunsubstituted or substituted C₆₋₁₀ aryl, unsubstituted or substituted5-10 membered heteroaryl, unsubstituted or substituted C₃₋₆ cycloalkylor unsubstituted or substituted 4-11 membered heterocycloalkyl, whereinthe substituted C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₆ cycloalkyl or4-11 membered heterocycloalkyl forming Cy is substituted with 1, 2, or 3substituents each independently selected from halogen, R^(Cy1), R^(Cy2),C₁₋₆ haloalkyl, CN, OH, and C₁₋₆ alkoxy, wherein each R^(Cy1) is,independently, C₁₋₆ alkyl, each of which is independently unsubstitutedor substituted with 1, 2 or 3 substituents independently selected fromhalogen, CN, OR^(a1), wherein each R^(Cy2) is, independently, C₆₋₁₀aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, or 4-7 memberedheterocycloalkyl, each of which is independently unsubstituted orsubstituted with 1, 2 or 3 substituents independently selected fromhalogen, C₁₋₆ alkyl, CN and OR^(a1), and wherein R^(a1) isindependently, at each occurrence, selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R³ is C₁₋₆ alkyl, Cy, or -L-Cy, wherein Cy isunsubstituted or substituted C₆₋₁₀ aryl, unsubstituted or substituted5-10 membered heteroaryl, unsubstituted or substituted C₃₋₆ cycloalkylor unsubstituted or substituted 4-11 membered heterocycloalkyl, whereinthe substituted C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₆ cycloalkyl or4-11 membered heterocycloalkyl forming Cy is substituted with 1, 2, or 3substituents each independently selected from halogen, R^(Cy1), C₆₋₁₀aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl or 4-7 memberedheterocycloalkyl, C₁₋₆ haloalkyl, CN, OH, and C₁₋₆ alkoxy, wherein eachR^(Cy1) is, independently, C₁₋₆ alkyl, each of which is independentlyunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from halogen, CN, and OR^(a1), and wherein R^(a1) isindependently, at each occurrence, selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R³ is C₁₋₆ alkyl.

In some embodiments, R³ is ethyl or isopropyl.

In some embodiments, R³ is Cy.

In some embodiments, R³ is -L-Cy.

In some embodiments, Cy is unsubstituted or substituted C₆₋₁₀ aryl.

In some embodiments, Cy is unsubstituted phenyl.

In some embodiments, Cy is substituted phenyl.

In some embodiments, Cy is phenyl substituted with 1, 2, or 3substituents.

In some embodiments, Cy is phenyl substituted with 1, 2, or 3substituents independently selected from halogen, CN, and OR^(a1).

In some embodiments, Cy is phenyl substituted with 1, 2, or 3substituents independently selected from fluoro, CN, and OH.

In some embodiments, Cy is 2-cyanophenyl, 2,6-difluorophenyl or2,6-difluoro-4-methoxyphenyl.

In some embodiments, Cy is unsubstituted or substituted 5-10 memberedheteroaryl.

In some embodiments, Cy is unsubstituted or substituted 5-10 memberedheteroaryl, the ring atoms of which consist of carbon atoms and 1 or 2nitrogen atoms.

In some embodiments, Cy is unsubstituted or substituted pyridinyl orpyrazolyl.

In some embodiments, Cy is unsubstituted pyridinyl.

In some embodiments, Cy is pyridinyl substituted with 1 substituentselected from R^(Cy2) and OR^(a1).

In some embodiments, Cy is 6-(morpholin-4-yl)pyridin-3-yl or6-methoxypyridin-3-yl.

In some embodiments, Cy is pyrazolyl substituted with a C₁₋₆ alkylgroup.

In some embodiments, Cy is 1-methyl-1H-pyrazol-4-yl or1-ethyl-1H-pyrazol-4-yl.

In some embodiments, Cy is unsubstituted or substituted C₃₋₆ cycloalkyl.

In some embodiments, Cy is unsubstituted or substituted 4-11 memberedheterocycloalkyl.

In some embodiments, Cy is unsubstituted or substitutedheterocycloalkyl, the ring atoms of which consist of carbon atoms and 1,2, or 3 heteroatoms independently selected from N and O.

In some embodiments, Cy is unsubstituted or substitutedheterocycloalkyl, the ring atoms or which consist of carbon atoms and 1or 2 nitrogen atoms.

In some embodiments, Cy is unsubstituted or substitutedheterocycloalkyl, the ring atoms of which consist of carbon atoms, 1oxygen atom and 1 nitrogen atom.

In some embodiments, a nitrogen atom of Cy forms the bond between Cy andthe remainder of the molecule.

In some embodiments, Cy is unsubstituted or substituted pyrrolidinyl,piperidinyl, azetidinyl, piperazinyl or oxopiperazinyl.

In some embodiments, Cy is unsubstituted pyrrolidin-1-yl.

In some embodiments, Cy is pyrrolidin-1-yl substituted with a C₁₋₆haloalkyl group.

In some embodiments, Cy is 3-(trifluoromethyl)pyrrolidin-1-yl.

In some embodiments, Cy is unsubstituted piperidin-1-yl.

In some embodiments, Cy is substituted piperidin-1-yl substituted at the4-position.

In some embodiments, Cy is substituted piperidin-1-yl substituted at the4-position by 1 substituent.

In some embodiments, Cy is substituted piperidin-1-yl substituted by 1substituent selected from R^(Cy2), CN, and OR^(a).

In some embodiments, Cy is 4-hydroxypiperidin-1-yl,4-cyanopiperidin-1-yl, 4-methoxypiperidin-1-yl,4-(pyridin-4-yl)piperidin-1-yl, or 4-(morpholin-4-yl)piperidin-1-yl.

In some embodiments, Cy is unsubstituted azetidin-1-yl.

In some embodiments, Cy is azetidin-1-yl substituted with two C₁₋₆ alkylgroups.

In some embodiments, Cy is 3,3-dimethylazetidin-1-yl.

In some embodiments, Cy is unsubstituted or substituted piperazin-1-yl.

In some embodiments, Cy is 4-substituted piperazin-1-yl.

In some embodiments, Cy is a piperazin-1-yl substituted with at leastone C₁₋₆ alkyl.

In some embodiments, Cy is piperazin-1-yl substituted only at the4-position.

In some embodiments, Cy is piperazin-1-yl substituted only at the4-position and wherein the 4-substituent is C₁₋₆ alkyl.

In some embodiments, Cy is 4-methylpiperazin-1-yl or4-ethylpiperazin-1-yl.

In some embodiments, Cy is unsubstituted or substituted oxopiperazinyl.

In some embodiments, Cy is unsubstituted or substituted3-oxopiperazin-1-yl.

In some embodiments, Cy is 3-oxopiperazin-1-yl substituted only at the4-position and wherein the 4-substituent is C₁₋₆ alkyl.

In some embodiments, Cy is 4-methyl-3-oxopiperazin-1-yl or4-ethyl-3-oxopiperazin-1-yl.

In some embodiments, Cy is unsubstituted or substituted3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, ormorpholinyl.

In some embodiments, Cy is unsubstituted3-oxa-9-azaspiro[5.5]undecan-9-yl, 1-oxa-8-azaspiro[4.5]decan-8-yl ormorpholin-4-yl.

In some embodiments, Cy is unsubstituted or substitutedheterocycloalkyl, the ring atoms of which consist of carbon atoms and 1oxygen atom.

In some embodiments, Cy is unsubstituted or substitutedtetrahydro-2H-pyranyl.

In some embodiments, Cy is unsubstituted tetrahydro-2H-pyran-4-yl.

In some embodiments, L is unsubstituted C₁₋₆ alkylene or C₁₋₆ alkylenesubstituted with 1, 2 or 3 substituents independently selected from F,Cl, CN, OH and O(C₁₋₆ alkyl).

In some embodiments, L is unsubstituted C₁₋₆ alkylene.

In some embodiments, L is C₁₋₃ alkylene.

In some embodiments, L is C₁₋₂ alkylene.

In some embodiments, L is CH₂.

In some embodiments, each R^(Cy1) is C₁₋₆ alkyl.

In some embodiments, each R^(Cy1) is methyl or ethyl.

In some embodiments, each R^(Cy2) is 4 to 7 membered heterocycloalkyl.

In some embodiments, R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(b2),R^(c2), and R^(d2) are each independently selected from H and C₁₋₆alkyl.

In some embodiments, R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(b2),R^(c2), and R^(d2) are each independently selected from H and methyl.

The compounds of Formula (I) include the following compounds, andpharmaceutically acceptable salts thereof:

-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluorophenyl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropyl-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropenyl-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-yl-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-azetidin-1-ylquinoline-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)quinoline-2-carboxamide;-   N-(4-(3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(pyridin-3-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)quinoline-2-carboxamide;-   N-(4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(4-hydroxypiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)-1,5-naphthyridine-2-carboxamide;    and-   N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]quinoline-2-carboxamide.

The compounds of Formula (I) include the following compounds, andpharmaceutically acceptable salts thereof:

-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluorophenyl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropyl-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,    6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropenyl-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-yl-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-azetidin-1-ylquinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-1,5-naphthyridine-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)quinoline-2-carboxamide;-   N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)quinoline-2-carboxamide;-   N-(4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(pyridin-3-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)quinoline-2-carboxamide;-   N-(4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(4-hydroxypiperidin-1-yl)quinoline-2-carboxamide;-   N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)-1,5-naphthyridine-2-carboxamide;    and-   N-{4-[(3R,4R,5    S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]quinoline-2-carboxamide.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups are described. It is specifically intended thateach linking substituent include both the forward and backward forms ofthe linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to disclose each ofthe forms individually. Where the structure requires a linking group,the Markush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chain orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbamyl” refers to a group of formula —C(O)NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1}halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In someembodiments, aryl groups have from 6 to about 10 carbon atoms. In someembodiments aryl groups have 6 carbon atoms. In some embodiments arylgroups have 10 carbon atoms. In some embodiments, the aryl group isphenyl. In some embodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or2 heteroatom ring members independently selected from nitrogen, sulfurand oxygen. In some embodiments, the heteroaryl is a five-membered orsix-membered heteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl,oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline,naphthyridine (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-and 2,6-naphthyridine), indole, benzothiophene, benzofuran,benzisoxazole, imidazo[1,2-b]thiazole, purine, or the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl”, employed alone or in combination with otherterms, refers to a non-aromatic, saturated, monocyclic, bicyclic orpolycyclic hydrocarbon ring system, including cyclized alkyl and alkenylgroups. The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has nto m ring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcamyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl”, employed alone or in combination with otherterms, refers to non-aromatic ring or ring system, which may optionallycontain one or more alkenylene groups as part of the ring structure,which has at least one heteroatom ring member independently selectedfrom nitrogen, sulfur oxygen and phosphorus, and which has 4-10 ringmembers, 4-7 ring members or 4-6 ring members. Included inheterocycloalkyl are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfide group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidine,azepane, dihydrobenzofuran, dihydrofuran, dihydropyran, morpholine,3-oxa-9-azaspiro[5.5]undecane, 1-oxa-8-azaspiro[4.5]decane, piperidine,piperazine, oxopiperazine, pyran, pyrrolidine, quinuclidine,tetrahydrofuran, tetrahydropyran, 1,2,3,4-tetrahydroquinoline, tropane,and thiomorpholine.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

The following abbreviations may be used herein: AcOH (acetic acid); aq.(aqueous); atm. (atmosphere(s)); Boc (t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); Cbz (carboxybenzyl); calc. (calculated); Cs₂CO₃(cesium carbonate); d (doublet); dd (doublet of doublets); DCM(dichloromethane); DIAD (N,N′-diisopropyl azidodicarboxylate); DIC(N,N′-diisopropylcarbodiimide); DIPEA (N,N-diisopropylethylamine); DMAP(4-dimethylaminopyridine); DMF (N,N-dimethylformamide); ESI(electrospray ionization); Et (ethyl); Et₂O (diethyl ether); EtOAc(ethyl acetate); Fmoc (9-fluorenylmethylmethoxycarbonyl); g (gram(s)); h(hour(s)); H₂ (hydrogen gas); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid/hydrogen chloride); HPLC(high performance liquid chromatography); Hz (hertz); IPA (isopropylalcohol); J (coupling constant); K₂CO₃ (potassium carbonate); K₃PO₄(potassium phosphate); LiHMDS (Lithium hexamethyldisilazide); LCMS(liquid chromatography—mass spectrometry); LiAlH₄ (lithiumtetrahydroaluminate); LiBH₄ (lithium tetrahydroborate); m (multiplet); M(molar); MgSO₄ (magnesium sulfate); MS (Mass spectrometry); Me (methyl);MeCN (acetonitrile); MeI (methyl iodide); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); MoSO₄ (molybdenum sulfate) N (normal); N₂ (nitrogengas); NaHCO₃ (sodium bicarbonate); NaOH (sodium hydroxide); Na₂SO₄(sodium sulfate); NH₄OH (ammonium hydroxide); NH₄Cl (ammonium chloride);nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); Pd(palladium); pM (picomolar); PPh₃ (triphenylphosphine); PTFE(polytetrafluoroethylene); RP-HPLC (reverse phase high performanceliquid chromatography); t (triplet or tertiary); t-Bu (tert-butyl);t-BuOH (tert-butanol) TEA (triethylamine); TFA (trifluoroacetic acid);THF (tetrahydrofuran); TiCl₄ (titanium tetrachloride); g (microgram(s));μL (microliter(s)); M (micromolar); wt % (weight percent).

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in Scheme 1. In the process shown in Scheme 1, a suitablysubstituted aromatic or heteroaromatic carboxaldehyde 1-1 (X¹=halogen,e.g. chloro, bromo, iodo) can be converted to a compound of Formula 1-2(R=alkyl), e.g., by heating with a suitable alkyl bromopyruvate in thepresence of pyridine. The resulting ester of Formula 1-2 can behydrolyzed to a corresponding acid 1-3 under standard saponificationconditions also known to one skilled in the art. (Wuts et al). Thecarboxylic acid 1-3 can then be reacted with an appropriatelysubstituted aminopyridine 1-4 under conditions suitable for formation ofan amide bond to form an amide of Formula 1-5. Suitable combinations forforming the amide bond include, e.g., the methods used to form amidebonds in peptides as described, e.g., in Jones, Amino Acid and PeptideSynthesis, 2^(nd) Ed., Oxford University Press, 2002; and Jones, TheChemical Synthesis of Peptides (International Series of Monographs onChemistry) (Oxford University Press, 1994). An example of a suitablecoupling agent is HATU/DIPEA.

The amide of Formula 1-5 can be coupled to R³ under conditions suitablefor formation of a bond such as a C—C bond or C—N bond to form acompound of formula 1-6. Suitable conditions include organometalliccross coupling reactions. Suitable conditions for forming a C—C bondinclude, e.g., Suzuki conditions, Stille conditions, Sonogashiraconditions, Negishi conditions, Heck conditions and the like. Suitableconditions for formation of a C—N bond include, e.g., Buchwald-Hartwigamination conditions, and copper-mediated conditions, e.g. conditionsdescribed in D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters,Tetrahedron Lett. 1998, 39, 2933-2936 and P. Y. S. Lam, C. G. Clark, S.Saubern, J Adams, M P. P Winters, D. M. T. Chan, A. Combs, TetrahedronLet. 1998, 39, 2941-2944. The substitutions of compound 1-6 can befurther transformed to desired functional groups.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in Scheme 2. In the process shown in Scheme 2, a suitablysubstituted aromatic or heteroaromatic carboxaldehyde 2-1 can beconverted to a compound of Formula 2-2 (R=alkyl), e.g., by heating witha suitable alkyl bromopyruvate in the presence of pyridine. Theresulting ester of Formula 2-2 can be hydrolyzed to a corresponding acid2-3 under standard saponification conditions also known to one skilledin the art. (Wuts et al). The carboxylic acid 2-3 can then be reactedwith an appropriately substituted aminopyridine 2-4 under conditionssuitable for formation of an amide bond to form an amide of Formula 2-5,which corresponds to the compound of Formula (I). Suitable combinationsfor forming the amide bond include, e.g., the methods used to form amidebonds in peptides as described, e.g., in Jones, Amino Acid and PeptideSynthesis, 2^(nd) Ed., Oxford University Press, 2002; and Jones, TheChemical Synthesis of Peptides (International Series of Monographs onChemistry) (Oxford University Press, 1994). An example of a suitablecoupling agent is HATU/DIPEA. The substitutions of compound 2-5 can befurther transformed to desired functional groups.

Other compounds of Formula (I) can be prepared by appropriatemodifications of the synthetic route described above. For example,compounds according to Formula (I) with various functional groups can beprepared by suitable functional group interconversion reactions known toone of ordinary skill in the art, e.g., as described by Larock,Comprehensive Organic Transformations: A Guide to Functional GroupPreparations (Wiley, 1999); and Katritzky et al. (Ed.), ComprehensiveOrganic Functional Group Transformations (Pergamon Press 1996).

The synthetic methods illustrated by Scheme 1 can be applied to thesynthesis of quinoline compounds as shown in Scheme 3. A substitutedbenzaldehyde 3-1 (X¹=halogen, e.g. chloro, bromo, iodo) is heated withethyl bromopyruvate in the presence of pyridine to provide quinoline3-2. The resulting ester 3-2 is hydrolyzed to corresponding acid 3-3 andreacted with an appropriately substituted aminopyridine 3-4 undercoupling conditions to afford an amide 3-5. The amide of Formula 3-5 canbe coupled to R³ under conditions suitable for formation of a C—C bondor C—N bond to form compound 3-6. Suitable conditions for forming a C—Cbond include, e.g., Suzuki conditions, Stille conditions, Sonogashiraconditions, Negishi conditions, and the like. Suitable conditions forformation of a C—N bond include, e.g., Buchwald-Hartwig aminationconditions, and copper-mediated conditions, e.g. conditions described inD. M. T. Chan, K. L Monaco, R.-P. Wang, M. P. Winters, Tetrahedron Lett.1998, 39, 2933-2936 and P. Y. S. Lam, C. G. Clark, S. Saubem, J Adams,M. P. Winters, D. M. T. Chan, A. Combs, Tetrahedron Lett. 1998, 39,2941-2944. The substitutions of compound 3-6 can be further transformedto desired functional groups.

The synthetic method illustrated by Scheme 1 can be applied to thesynthesis of 1,5-naphthyridine compounds as shown in Scheme 4. Asubstituted picolinaldehyde 4-1 (X¹=halogen, e.g. chloro, bromo, iodo)is heated with ethyl bromopyruvate in the presence of pyridine toprovide naphthyridine 4-2. The resulting ester 4-2 is hydrolyzed tocorresponding acid 4-3 and reacted with an appropriately substitutedaminopyridine 4-4 under coupling conditions to afford an amide 4-5. Theamide of Formula 4-5 can be coupled to R³ under conditions suitable forformation of a C—C bond or C—N bond to form compound 4-6. Suitableconditions for forming a C—C bond include, e.g., Suzuki conditions,Stille conditions, Sonogashira conditions, Negishi conditions, and thelike. Suitable conditions for formation of a C—N bond include, e.g.,Buchwald-Hartwig amination conditions, and copper-mediated conditions,e.g. conditions described in D. M. T. Chan, K. L Monaco, R.-P. Wang, M.P. Winters, Tetrahedron Lett. 1998, 39, 2933-2936 and P. Y. S. Lam, C.G. Clark, S. Saubem, J Adams, M. P. Winters, D. M. T. Chan, A. Combs,Tetrahedron Lett. 1998, 39, 2941-2944. The substitutions of compound 4-6can be further transformed to desired functional groups.

The synthetic methods illustrated by Scheme 2 can be applied to thesynthesis of quinoline compounds as shown in Scheme 5. A substitutedbenzaldehyde 5-1 is heated with ethyl bromopyruvate in the presence ofpyridine to provide quinoline 5-2. The resulting ester 5-2 is hydrolyzedto corresponding acid 5-3 and reacted with an appropriately substitutedaminopyridine 5-4 under coupling conditions to afford an amide 5-5. Thesubstitutions on 5-5 can be further transformed to desired functionalgroups in the final product, or in any of the steps of the synthesis,using methods know to one skilled in the art.

The synthetic method illustrated by Scheme 2 can be applied to thesynthesis of 1,5-naphthyridine compounds as shown in Scheme 6. Asubstituted picolinaldehyde 6-1 is heated with ethyl bromopyruvate inthe presence of pyridine to provide naphthyridine 6-2. The resultingester 6-2 is hydrolyzed to corresponding acid 6-3 and reacted with anappropriately substituted aminopyridine 6-4 under coupling conditions toafford an amide 6-5. The substitutions on 6-5 can be further transformedto desired functional groups in the final product, or in any of thesteps of the synthesis, using methods know to one skilled in the art.

Starting materials, reagents and intermediates whose synthesis is notdescribed herein are either commercially available, known in theliterature, or may be prepared by methods known to one skilled in theart.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds of theinvention may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds of the invention. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

III. Uses of the Compounds

Compounds of the invention can inhibit the activity of one or moremembers of the Pim kinase family and, thus, are useful in treatingdiseases and disorders associated with activity of Pim kinases. For theuses described herein, any of the compounds of the invention, includingany of the embodiments thereof, may be used.

The compounds of the invention can inhibit one or more of Pim1, Pim2 andPim3. In some embodiments the compounds are selective for one Pim kinaseover another. “Selective” means that the compound binds to or inhibits aPim kinase with greater affinity or potency, respectively, compared to areference enzyme, such as another Pim kinase. For example, the compoundscan be selective for Pim1 over Pim2 and Pim3, selective for Pim2 overPim1 and Pim3, or selective for Pim3 over Pim1 and Pim2. In someembodiments, the compounds inhibit all of the Pim family members (e.g.,Pim1, Pim2 and Pim3). In some embodiments, the compounds can beselective for Pim over other kinases such as receptor and non-receptorSer/Thr kinases such as Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC,CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK and mTOR; receptor Tyrkinases such as EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR,PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2,FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4,EphA1, EphA2, EphA3, EphB2, EphB4, Tie2; and non-receptor Tyr kinasessuch as Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK or ABL. In general,selectivity can be at least about 5-fold, at least about 10-fold, atleast about 20-fold, at least about 50-fold, at least about 100-fold, atleast about 200-fold, at least about 500-fold or at least about1000-fold. The method of inhibiting a Pim1, Pim2 or Pim3 kinase includescontacting the appropriate enzyme with the compound of the invention, orany of the embodiments thereof, or a pharmaceutically acceptable saltthereof.

Thus, the present disclosure provides methods of treating a Pimkinase-associated disease or disorder in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the invention,or any of the embodiments thereof, or a pharmaceutical compositionthereof. The present disclosure also provides a compound of theinvention, or any of the embodiments thereof, or a pharmaceuticalcomposition thereof, for use in treating a Pim kinase-associated diseaseor disorder. Also provided is the use of a compound of the invention, orany of the embodiments thereof, or a pharmaceutical composition thereof,in the manufacture of a medicament for treating a Pim kinase-associateddisease or disorder.

A Pim kinase-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the Pim kinase, including overexpression and/or abnormalactivity levels. Abnormal activity levels can be determined by comparingactivity level in normal, healthy tissue or cells with activity level indiseased cells. A Pim kinase-associated disease can also include anydisease, disorder or condition that can be prevented, ameliorated,inhibited or cured by modulating Pim kinase activity. In someembodiments, the disease is characterized by the abnormal activity orexpression (e.g., overexpression) of one or more Pim1, Pim2 and Pim3. Insome embodiments, the disease is characterized by mutant Pim1, Pim2 orPim3. A Pim kinase associated disease can also refer to any disease,disorder or condition wherein modulating the expression or activity ofone or more Pim kinases is beneficial.

Pim kinase associated diseases that can be treated using the compoundsof the invention include cancer, including, in particular, cancers inwhich Pim kinases are upregulated or an oncogene, e.g., Myc or Bcl2, isactivated. Pim kinase associated diseases include solid tumors, e.g.,prostate cancer, colon cancer, esophageal cancer, endometrial cancer,ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreaticcancer, gastric cancer, breast cancer, lung cancer, cancers of the heador neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc. Pimkinase associated diseases also include hematological cancers, e.g.,lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acutemyelogenous leukemia (A ML), chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (C ML), diffuse large B-cell lymphoma (DLBCL),mantle cell lymphoma, non-Hodgkin lymphoma (including relapsednon-Hodgkin lymphoma, refractory non-Hodgkin lymphoma and recurrentfollicular non-Hodgkin lymphoma), Hodgkin lymphoma and multiple myeloma.

Pim kinase associated diseases that can be treated using the compoundsof the invention also include myeloproliferative disorders such aspolycythemia vera (PV), essential thrombocythemia (ET), chronicmyelogenous leukemia (C ML) and the like. The myeloproliferativedisorder can be myelofibrosis such as primary myelofibrosis (PMF),myelofibrosis with myeloid metaplasia (MMM), post-polycythemiavera/essential thrombocythemia myelofibrosis (Post-PV/ET MF),post-essential thrombocythemia myelofibrosis (Post-ET MF) orpost-polycythemia vera myelofibrosis (Post-PV MF).

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include immune disorders such asautoimmune diseases. The immune disorders include multiple sclerosis,rheumatoid arthritis, allergy, food allergy, asthma, lupus, inflammatorybowel disease and ulcerative colitis.

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include atherosclerosis.

The compounds of the invention can also be used to inhibit diseaseprocesses in which Pim-kinases are involved, including angiogenesis andtumor metastasis.

Due to the fact that Pim kinases are regulated by the JAK/STAT pathway,the compounds of the invention are useful to treat diseases in whichmodulating JAK/STAT signaling is beneficial. Thus, other diseases thatcan be treated using the compounds of the invention include Crohn'sdisease, irritable bowel syndrome, pancreatitis, diverticulosis, Grave'sdisease, juvenile rheumatoid arthritis, osteoarthritis, psoriaticarthritis, ankylosing spondylitis, myasthenia gravis, vasculitis,autoimmune thyroiditis, dermatitis, psoriasis, scleroderma, systemicsclerosis, vitiligo, graft versus host disease, Sjogren's syndrome,glomerulonephritis and diabetes mellitis (type I).

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease. In one embodiment, treating or treatmentincludes preventing or reducing the risk of developing the disease;e.g., preventing or reducing the risk of developing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine different kinase inhibitors,exhibiting different preferences in the kinases which they modulate theactivities of, to treat such conditions. Targeting more than onesignaling pathway (or more than one biological molecule involved in agiven signaling pathway) may reduce the likelihood of drug-resistancearising in a cell population, and/or reduce the toxicity of treatment.

Accordingly, the Pim inhibitors of the present invention can be used incombination with one or more other kinase inhibitors for the treatmentof diseases, such as cancer, that are impacted by multiple signalingpathways. For example, the compounds of the invention can be combinedwith one or more inhibitors of the following kinases for the treatmentof cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1,FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB,TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2,Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.Additionally, the Pim inhibitors of the invention can be combined withinhibitors of kinases associated with the PIK3/Akt/mTOR signalingpathway, such as PI3K, Akt (including Akt1, Akt2 and Akt3) and mTORkinases.

The Pim inhibitors of the present invention can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation or surgery. The compounds can be administeredin combination with one or more anti-cancer drugs, such as achemotherapeutics. Example chemotherapeutics include any of: abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

The Pim inhibitors of the present invention can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic anti-bodies.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, sequentially, or in combination(e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thus thepresent disclosure provides a composition comprising a compound Formula(I), or a pharmaceutically acceptable salt thereof, or any of theembodiments thereof, and at least one pharmaceutically acceptablecarrier. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier. In some embodiments, the composition comprises at least onecompound described herein, or a pharmaceutically acceptable saltthereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™).

In some embodiments, the polyethylene oxide is polyethylene oxide WSR1105 (e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders.

The liquid or solid compositions may contain suitable pharmaceuticallyacceptable excipients as described supra. In some embodiments, thecompositions are administered by the oral or nasal respiratory route forlocal or systemic effect. Compositions can be nebulized by use of inertgases. Nebulized solutions may be breathed directly from the nebulizingdevice or the nebulizing device can be attached to a face mask, tent, orintermittent positive pressure breathing machine. Solution, suspension,or powder compositions can be administered orally or nasally fromdevices which deliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the invention can further be useful in investigationsof biological processes, including kinase signaling, in normal andabnormal tissues. Thus, another aspect of the present invention relatesto labeled compounds of the invention (radio-labeled,fluorescent-labeled, etc.) that would be useful not only in imagingtechniques but also in assays, both in vitro and in vivo, for localizingand quantitating Pim kinases in tissue samples, including human, and foridentifying Pim kinase ligands by inhibition binding of a labeledcompound. Accordingly, the present invention includes Pim kinase assaysthat contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro Pim kinase labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2 or 3 deuterium atoms. Synthetic methods forincorporating radio-isotopes into organic compounds are known in theart.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a Pim-kinase bymonitoring its concentration variation when contacting with the Pimkinase, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a Pim kinase (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the Pim kinase directly correlatesto its binding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of Pim kinase-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula (I), or any of the embodimentsthereof. Such kits can further include one or more of variousconventional pharmaceutical kit components, such as, e.g., containerswith one or more pharmaceutically acceptable carriers, additionalcontainers, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, can also be included in thekit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to bePim-kinase inhibitors according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

Intermediate 1 tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methyl-piperidin-3-yl]carbamate

Step 1. 1-tert-butyl 2-methyl (2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate (16.1 g, 66.2 mmol) in THF (100mL) was cooled to −78° C. LiHMDS in THF (1.0 M, 68.2 mL, 68.2 mmol) wasadded dropwise over 5 min. The resulting mixture was stirred at −78° C.for 35 min., then MeI (10.0 mL, 160 mmol) was added. The reaction waswarmed to room temperature slowly overnight. The reaction was quenchedwith AcOH (7.5 mL, 130 mmol) and water (5 mL) and then the mixtureconcentrated under reduced pressure. The concentrated residue wasfurther diluted with water and extracted with EtOAc (3 times). Thecombined extracts were washed with water and brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column and eluted with 0-50% EtOAc/Hexanes over45 min. Fractions were checked by TLC (MoSO₄ stain) and LCMS. 6.1 g (35%yield) of the sub-title compound was obtained. LCMS calc. for C₇H₁₂NO₃(M+H-Boc+H)⁺: m/z=158.1; found: 158.1.

Step 2. tert-Butyl [(S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate

A solution of 1-tert-butyl 2-methyl(2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (11.0 g, 42.8 mmol)in THF (100 mL) was cooled to 0° C. then LiBH₄ (2.8 g, 130 mmol) andthen EtOH (22 mL) were added. The mixture was slowly allowed to warm toroom temperature and stirred for 4 h. The reaction was quenched withwater then extracted with EtOAc (3 times). The combined extracts weredried over Na₂SO₄, filtered, and concentrated under reduced pressure togive 4.5 g (45% yield) of the crude sub-title compound. The crudeproduct was used without further purification.

Step 3. tert-Butyl [(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate

A solution of tert-butyl[(1S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate (9.50 g,40.7 mmol) in DCM (200 mL) was cooled to 0° C. TEA (23 mL, 160 mmol) wasadded, followed by dropwise addition of methanesulfonyl chloride (9.4mL, 120 mmol). The clear solution became cloudy and yellow and themixture was stirred at 0° C. for 1 h. The mixture was diluted with DCMand washed with saturated aq. NaHCO₃ and water. The organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure togive an intermediate mesylate as a yellow oil that was used immediatelyfor the next step. The intermediate mesylate and benzylamine (90 mL, 800mmol) were combined in microwave vial, sealed and heated at 70° C.overnight. After 18 h, the mixture was quenched with 10% aq. NaOH. Themixture was then extracted with hexanes (3 times). The combined extractswere washed with brine, dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was purified on a silica gel columnand eluted with 0-40% EtOAc/hexane over 34 min. to give 6.0 g (49%yield) of the sub-title compound as a white solid. LCMS calc. forC₁₈H₂₉N₂O₂ (M+H)⁺: m/z=305.2; found: 305.1.

Step 4. tert-Butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate

A mixture of tert-butyl[(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate (4.5 g, 15 mmol),AcOH (2.0 mL, 35 mmol) and 10% Pd on carbon (1.6 g, 1.5 mmol) in EtOH(100 mL) was stirred in a Par-shaker under H₂ (50 psi) overnight. Themixture was filtered through a pad of diatomaceous earth andconcentrated under reduced pressure. The residue was diluted with DCM(500 mL) and washed with saturated aq. NaHCO₃ solution. The aqueouslayer was extracted twice with DCM. The combined DCM extract was driedover Na₂SO₄ and concentrated under reduced pressure to give 2.2 g (67%yield) of the sub-title compound as a white solid. LCMS calc. forC₁₁H₂₃N₂O₂ (M+H)⁺: m/z=: 215.2; found: 215.1.

Step 5. tert-Butyl[(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitropyridine (740 mg, 4.7 mmol), tert-butyl[(3S,5R)-5-methylpiperidin-3-yl]carbamate (1000.0 mg, 4.67 mmol) andDIPEA (2.4 mL, 14 mmol) was irradiated in a microwave oven for 1 h at130° C. The reaction mixture was concentrated under reduced pressure andthe residue was purified by column chromatography on silica gel using aCombiFlash® apparatus eluting with EtOAc/hexane (10-60%). Thepurification gave 1.21 g (80% yield) of the sub-title compound as acolorless oil. LCMS calc. for C₁₆H₂₅N₄O₄ (M+H)⁺: m/z 337.2; found:337.1.

Step 6. tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

A mixture of tert-butyl[(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (100mg, 0.3 mmol), iron powder (0.072 g, 1.3 mmol), AcOH (2.0 mL, 35 mmol)and water (0.2 mL, 10 mmol) was stirred at room temperature for 60 min.When the reaction was complete, the reaction mixture was concentratedunder reduced pressure, diluted with EtOAc, filtered through a pad ofdiatomaceous earth, washed with aqueous NaHCO₃ solution, washed withwater and brine, dried over Na₂SO₄, and concentrated under reducedpressure to give 60 mg (60% yield) of the title compound as a brownsolid. LCMS calc. for C₁₆H₂₇N₄O₂ (M+H)⁺: m/z 307.1; found: 307.1.

Intermediate 2N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-bromo-1,5-naphthyridine-2-carboxamide

Step 1. 7-Bromo-1,5-naphthyridine-2-carboxylic acid

To a solution of 1,5-naphthyridine-2-carboxylic acid (from PrincetonBio, Catalogue Number PBMR019135; 0.87 g, 5.0 mmol) in AcOH (20 mL) wasadded N-bromosuccinimide (1.1 g, 6.0 mmol). The mixture was stirred at120° C. overnight. The reaction was concentrated under reduced pressure,treated with EtOAc (30 mL), and filtered to afford the crude product aswhite solid which was used in the next step without furtherpurification. LCMS calc. for C₉H₆BrN₂O₂[M+H]⁺ m/z: 253.1; found 253.1.

Step 2.N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-bromo-1,5-naphthyridine-2-carboxamide

To a solution of 7-bromo-1,5-naphthyridine-2-carboxylic acid (510 mg,2.0 mmol) and tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (670mg, 2.2 mmol) in DMF (12.0 mL) was added DIPEA (650 mg, 5.0 mmol) andHATU (912 mg, 2.40 mmol). The reaction mixture was stirred at roomtemperature for 2 h and was then concentrated under reduced pressure.The mixture was dissolved in DCM (10 mL) and TFA (1.54 mL, 20.0 mmol)was added. The reaction mixture was stirred at 50° C. for 1 h. Themixture was then concentrated under reduced pressure and purified bychromotography (MeOH/DCM 5-20%) to afford the title compound ascolorless solid (650 mg, 74%). LCMS calc. for C₂₀H₂₂BrN₆O [M+H]⁺ m/z:441.1; found 441.1.

Intermediate 3 tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

Step 1. tert-Butyl (4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-hydroxy-2-methyl-3-oxopropyl}-2, 2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of (R)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone (12 g, 51mmol) in DCM (300 mL) (0.13 M), 1.0 M TiCl₄ in DCM (51 mL, 51 mmol) wasadded at −40° C. The mixture was stirred at −40° C. for 10 min., thenDIPEA (22 mL, 130 mmol) was added, forming a dark red solution. Themixture was stirred at 0° C. for 20 min. tert-Butyl(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (12 g, 51 mmol)in DCM (100 mL) (0.5 M) was then added dropwise and the resultingmixture was stirred for 1.5 h at 0° C. LCMS showed 2 peaks with the masscorresponding to the title compound, one major peak and one minor peak(5:2). The reaction mixture was quenched by the addition of aq. NH₄Clsolution and the mixture was extracted with DCM. The organic phase wasseparated, washed with brine, dried over MgSO₄, concentrated underreduced pressure, and purified by chromatography on silica gel (0-40%EtOAc/hexane) to give 8 g (30% yield) of the sub-title compound as acolorless oil. LCMS calc. for C₂₄H₃₅N₂O₇ (M+H)⁺: m/z=463.2; found:463.1.

Step 2. tert-Butyl (4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-3-oxopropyl)-2,2-dimethyl-1, 3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-hydroxy-2-methyl-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(12.1 g, 26.2 mmol) and 2,6-lutidine (5.4 mL, 47 mmol) in DCM (260 mL)(0.1 M) was added tert-butyldimethylsilyl trifluoromethanesulfonate(8.41 mL, 36.6 mmol) at −40° C. The mixture was stirred at −40° C. for 2h. The reaction mixture was diluted with DCM, washed with saturated aq.NaHCO₃ solution, dried over Na₂SO₄, concentrated under reduced pressure,and purified by chromatography on silica gel (0-20% EtOAc/hexane) togive 14 g (92.8% yield) of the sub-title compound as a colorless gel.LCMS calc. for C₂₅H₄₁N₂O₅Si (M+H-Boc+H)⁺: m z 477.3; found: 477.1.

Step 3. tert-Butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1, 3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (14.0 g, 24.3 mmol) and EtOH(4.2 mL, 73 mmol) in THF (300 mL) (0.09 M) was added LiBH₄ (1.6 g, 73mmol) at −30° C. The mixture was allowed to warm to 0° C. and stirredovernight. The reaction mixture was diluted with ether and 1 M NaOH wasadded. The resulting mixture was extracted with EtOAc and the organicextract was washed with brine, dried over Na₂SO₄, concentrated underreduced pressure, and purified by chromatography on silica gel (0-20%EtOAc/hexane) to give 4.1 g (42% yield) of the sub-title compound as acolorless oil. LCMS calc. for C₁₅H₃₄NO₃Si (M+H-Boc+H)⁺: m/z=304.2;found: 304.1.

Step 4. tert-Butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2,2-dimethyl-1, 3-oxazolidine-3-carboxylate

To a mixture of tert-butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(8.20 g, 20.3 mmol), diisopropyl azodicarboxylate (8.0 mL, 41 mmol) andPPh₃ (11 g, 41 mmol) in THF (100 mL) (0.18 M), diphenylphosphonic azide(8.8 mL, 41 mmol) was added. The mixture was stirred at room temperatureovernight. The mixture was concentrated under reduced pressure, and theresidue was purified by chromatography on silica gel (0-15%EtOAc/hexane) to give 5.2 g (60% yield) of the sub-title compound as ayellowish oil. LCMS calc. for C₂₀H₄₁N₄O₄Si (M+H)⁺: m/z=429.3; found:429.1.

Step 5. tert-Butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate

To a solution of tert-butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(10.5 g, 24.5 mmol) in EtOH (70 mL) was added pyridiniump-toluenesulfonate (12.3 g, 49.0 mmol) and the mixture was then heatedunder reflux for 2 days.

The volatile solvents were removed under reduced pressure and theresidue was dissolved in DCM (200 mL, 0.1 M). To the resulting solutionwere added DIPEA (8.53 mL, 49.0 mmol) and di-tert-butyldicarbonate (6.42g, 29.4 mmol). The reaction mixture was stirred at room temperature for5 h. The mixture was concentrated under reduced pressure and purified bychromatography on silica gel (0-25% EtOAc/Hexane) to give 5.8 g (61%yield) of the sub-title compound as a colorless oil. LCMS calc. forC₁₂H₂₉N₄O₂Si (M+H-Boc+H)⁺: m/z=289.2; found: 289.1.

Step 6.(2R,3R,4S)-5-Azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentylmethanesulfonate

To a solution of tert-butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate(5.80 g, 14.9 mmol) in pyridine (75 mL) at 0° C. was addedmethanesulfonyl chloride (1.50 mL, 19.4 mmol) and DMAP (0.36 g, 3.0mmol). The mixture was stirred at 0° C. for 1 h. The solution wasdiluted with EtOAc, washed with saturated NaHCO₃ solution, concentratedunder reduced pressure and purified by chromatography on silica gel(0-25% EtOAc/Hexane) to give 4.8 g (69% yield) of the sub-title compoundas a colorless oil. LCMS calc. for C₁₃H₃₁N₄O₄SSi (M+H-Boc)⁺: m/z=367.2;found: 367.2.

Step 7. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A solution of(2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentylmethanesulfonate (4.25 g, 9.11 mmol) in MeOH (100 mL) (0.09M) wasdeoxygenated with a stream of N₂ for 20 min. DIPEA (4.0 mL, 23 mmol) wasadded, followed by 10% Pd on carbon (0.97 g, 0.91 mmol). The reactionmixture was stirred under a balloon containing H₂ for 2 h. The solutionwas filtered through a pad of diatomaceous earth and rinsed with MeOH.The filtrate was concentrated under reduced pressure to give 2.10 g (66%yield) of the sub-title compound as a white solid. LCMS calc. forC₁₇H₃₇N₂O₃Si (M+H)⁺: m/z=345.3; found: 345.1.

Step 8. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitropyridine (150.0 mg, 0.9461 mmol) andtert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(300.0 mg, 0.8707 mmol) and TEA (0.3763 mL, 2.700 mmol) in IPA (10.0 mL)was stirred at 60° C. for 2 h. The reaction mixture was concentratedunder reduced pressure and the residue was purified by columnchromatography on silica gel using a CombiFlash® apparatus (eluting with0 to 30% EtOAc in hexane) to give 100 mg (24% yield) of the sub-titlecompound. LCMS calc. for C₂₂H₃₉N₄O₅Si (M+H)⁺: m/z=467.3; found: 467.1.

Step 9. tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A mixture of tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate(100.00 mg, 0.27858 mmol), AcOH (10.00 mL) and iron powder (558.4 mg,9.999 mmol) was stirred at ambient temperature for 2 h. The mixture wasdiluted with 30 mL of EtOAc and filtered through a pad of diatomaceousearth. The combined organic filtrate was then concentrated under reducedpressure. The residue was diluted with EtOAc and washed with aq. Na₂CO₃solution and 0.2 M NaOH. The organic phase was concentrated underreduced pressure to give 50 mg (47% yield) of the title compound. LCMScalc. for C₂₂H₄₁N₄O₃Si (M+H)⁺: m/z=437.3; found: 437.1.

Intermediate 4N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-bromo-1,5-naphthyridine-2-carboxamide

To a solution of 7-bromo-1,5-naphthyridine-2-carboxylic acid (1700 mg,6.9 mmol) and tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(2500 mg, 5.7 mmol) in DMF (50 mL) was added DIPEA (1.8 g, 14.0 mmol)and HATU (2.4 g, 6.2 mmol). The reaction mixture was stirred at roomtemperature for 2 h before it was concentrated under reduced pressure.The mixture was dissolved in DCM (50 mL) and TFA (5.32 mL, 69 mmol) wasadded. The reaction was then stirred at 50° C. for 1 h before it wasconcentrated under reduced pressure and purified by chromotography(MeOH/DCM 5-20%) to afford the title product as colorless solid (1.80 g,69%). LCMS calc. for C₂₀H₂₂BrN₆O₂[M+H]⁺ m/z: 457.1; found 457.1.

Intermediate 5 tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate

Step 1. tert-Butyl (4R)-4-{(R, 2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-cyclopropyl-1-hydroxy-3-oxopropyl}-2, 2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of(4R)-4-benzyl-3-(cyclopropylacetyl)-1,3-oxazolidin-2-one (2.0 g, 7.7mmol) in anhydrous DCM (45 mL) at −40° C. was added a solution of 1.0 MTiCl₄ in DCM (9.3 mL) dropwise under an atmosphere of N₂, forming ayellow slurry. After 10 min., DIPEA (3.36 mL, 19.3 mmol) was addeddropwise, changing the color from yellow to deep purple. The reactionmixture was allowed to gradually warm to −20° C. while stirring over 1h. The reaction mixture was then cooled to −40° C. prior to the dropwiseaddition of a solution of tert-butyl(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.8 g, 7.85mmol) (Aldrich cat#462063) in anhydrous DCM (5 mL). The reaction mixturewas allowed to gradually warm to 0° C. for 1 h and then stirred for anadditional 1.5 h at 0° C. The reaction was quenched by the addition ofsaturated aq. NH₄Cl (15 mL). After separation of the two layers thatformed, the organic layer was washed with water and brine, dried overNa₂SO₄, concentrated under reduced pressure, and purified by flashchromatography (120 g silica gel, eluting with 0-60% EtOAc/hexanes) toafford the sub-title compound (1.9 g, 50%). LCMS (ESI) calc. forC₂₆H₃₆N₂O₇Na (M+Na)⁺: m/z 511.2, found 511.1.

Step 2. tert-Butyl (4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-oxopropyl)-2,2-dimethyl-1, 3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-cyclopropyl-1-hydroxy-3-oxopropyl)}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.80 g, 3.68 mmol) in anhydrous DCM (10 mL) at −40° C., 2,6-lutidine(0.85 mL, 7.3 mmol) was added under an atmosphere of N₂. After 10 min.,a solution of tert-butyldimethylsilyl trifluoromethanesulfonate (1.1 mL,4.9 mmol) in anhydrous DCM (1 mL) was added. The reaction mixture wasallowed to warm gradually to ambient temperature while stirringovernight. The crude reaction mixture was diluted with1,2-dichloroethane and cooled to 0° C., then quenched with saturated aq.NaHCO₃. After separation of the two layers, the organic layer was washedwith water and brine, dried over Na₂SO₄, concentrated under reducedpressure, and purified by flash chromatography (120 g silica gel,eluting with 0-30% EtOAc/hexanes) to afford the sub-title compound (2.1g, 95%). LCMS (ESI) calc. for C₃₂H₅₀N₂O₇SiNa (M+Na)⁺: m/z=625.3, found625.1.

Step 3. tert-Butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-hydroxypropyl)-2,2-dimethyl-1, 3-oxazolidine-3-carboxylate

A solution of tert-butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(3.3 g, 5.5 mmol) in anhydrous THF (50 mL) and EtOH (1 mL) under anatmosphere of N₂ was cooled to −30° C. prior to the addition of LiBH₄(0.24 g, 11 mmol). The reaction mixture was gradually warmed to ambienttemperature while stirring for 20 h. The crude reaction mixture wasdiluted with Et₂O (36 mL) and cooled to 0° C. prior to the addition of 1M aq. NaOH (36 mL). After separation of the layers, the aqueous layerwas extracted with EtOAc several times and the combined organic extractswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography (120 g silica gel, eluting with 0-40% EtOAc/hexanes) toafford the sub-title compound (1.27 g, 54%). LCMS (ESI) calc. forC₂₂H₄₃NO₅SiNa (M+Na)⁺: 452.3, found 452.0.

Step 4. tert-Butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylpropyl)-2,2-dimethyl-1, 3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.3 g, 3.0 mmol) and PPh₃ (1.6 g, 6.1 mmol) in anhydrous THF (20 mL)was added diisopropyl azodicarboxylate (1.2 mL, 5.9 mmol) dropwise underan atmosphere of N₂. Upon completion of the addition, a precipitate wasformed. The reaction mixture was stirred for 30 min. prior to theaddition of a solution of diphenylphosphonic azide (1.3 mL, 6.2 mmol) inanhydrous THF (1.0 mL). After stirring at ambient temperature for 3 h,the volatile organic solvents were removed under reduced pressure andthe crude product was purified by flash column chromatography (120 g ofsilica gel, eluting with 0-15% EtOAc-hexanes) to afford the sub-titlecompound as a light yellow oil (1.18 g, 86%). LCMS (ESI) calc. forC₁₇H₃₅N₄O₂Si (M+H-Boc+H)⁺: 355.30, found 355.1.

Step 5. tert-Butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclopropyl-1-(hydroxymethyl)butyl]carbamate

To a solution of tert-butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.16 g, 2.55 mmol) in MeOH (5 mL) at 0° C. was added TFA (4.9 mL, 64mmol) and the resulting solution was stirred at ambient temperature for1 h. The volatile organic solvents were removed under reduced pressureand the residue was azeotropically washed with toluene (2×3 mL). Theresidue was dissolved in anhydrous DCM (18 mL), then DIPEA (0.99 g, 7.6mmol) and di-tert-butyldicarbonate (0.84 g, 3.8 mmol) were added and theresulting solution was stirred at ambient temperature for 1 h. Thevolatile solvents were removed under reduced pressure and the crudeproduct was purified by flash column chromatography (120 g silica gel,eluting with 0-100% EtOAc/hexanes) to afford the sub-title compound(0.57 g, 54%) and the desilylated product (0.2 g, 26%). LCMS (ESI) calc.for C₁₄H₃₁N₄O₂Si (M+H-Boc+H)⁺: m/z=315.3, found 315.0.

Step 6.tert-Butyl-(2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-cyclopropylpentylmethanesulfonate

To a solution of tert-butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)-14-sulfanyl]oxy}-3-cyclopropyl-1-(hydroxymethyl)butyl]carbamate(0.240 g, 0.573 mmol) in anhydrous pyridine (2.0 mL) −20° C. was addedDMAP (0.014 g, 0.11 mmol) and methanesulfonyl chloride (0.044 mL, 0.57mmol). The reaction mixture was allowed to warm gradually to 5° C. andstirred for 2 h. The crude reaction mixture was diluted with EtOAc andconcentrated under reduced pressure onto silica gel and purified byflash column chromatography (24 g silica gel, eluting with 0-20%EtOAc-hexanes) to afford the sub-title compound (0.240 g, 86%). LCMS(ESI) calc. for C₁₅H₃₃N₄O₄SSi (M+H-Boc+H)⁺: m/z=393.2; found 393.0.

Step 7.((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate

A solution of(2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-cyclopropylpentyl methanesulfonate (0.250 g,0.507 mmol) and DIPEA (0.26 mL, 1.5 mmol) in MeOH (8.0 mL) was purgedwith N₂ prior to the addition of 10% Pd (dry basis) on activated carbon,wet, Degussa type E101 NE/W (0.080 g, 0.076 mmol). The reaction mixturewas stirred under an atmosphere of H₂ via a balloon for 2 h. Theinorganics were then filtered off, rinsed thoroughly with MeOH andEtOAc, and the filtrate was concentrated under reduced pressure toafford the sub-title compound (0.244 g). LCMS (ESI) calc. forC₁₉H₃₉N₂O₃Si (M+H)⁺: m/z=371.3, found 371.1. ¹H NMR (500 MHz, CDCl₃) δ4.56 (s, 1H), 3.36-3.23 (m, 3H), 3.04 (dd, J=13.0, 3.1 Hz, 1H), 2.35(ddd, J=14.7, 12.5, 11.0 Hz, 2H), 1.43 (s, 9H), 0.75 (tt, J=9.4, 4.7 Hz,1H), 0.63-0.52 (m, 1H), 0.47 (ddt, J=13.0, 8.2, 4.1 Hz, 1H), 0.38 (qd,J=9.2, 5.5 Hz, 2H), 0.08-−0.02 (m, 1H) ppm.

Step 8. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate

A mixture of tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(0.180 g, 0.486 mmol), 4-chloro-3-nitropyridine (0.10 g, 0.63 mmol) andTEA (0.20 mL, 1.4 mmol) in IPA (1.8 mL) was heated at 75° C. in a sealedvial for 1 h. After cooling to ambient temperature, the reaction mixturewas diluted with EtOAc (40 mL) and water (3 mL). The layers that formedwere separated, the organic layer was washed with water (2×3 mL) and thecombined aqueous phases were back extracted with EtOAc (3 mL). Thecombined organic layers were washed with brine (3 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by flash column chromatography (20 g silica gelcolumn, eluting with 0-20% EtOAc/hexanes) to afford the sub-titlecompound (0.135 g, 56%). LCMS (ESI) calc. for C₂₄H₄₁N₄O₅Si (M+H)⁺:m/z=493.3, found 493.1.

Step 9. tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate

A mixture of tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate(0.140 g, 0.284 mmol) and 10% Pd (dry basis) on activated carbon, wet,Degussa type E101 NE/W (0.040 g, 0.038 mmol) in MeOH (3.5 mL) and EtOAc(0.5 mL) was purged with N₂ prior to stirring under an atmosphere of H₂(introduced via a balloon) overnight. The crude reaction mixture wasfiltered through a pad of diatomaceous earth and the inorganics werewashed thoroughly with EtOAc. The filtrate was concentrated underreduced pressure afford the sub-title compound (0.125 g, 95%). LCMS(ESI) calc. for C₂₄H₄₃N₄O₃Si (M+H)⁺: m/z=463.3, found 463.1.

Example 1N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluorophenyl)-1,5-naphthyridine-2-carboxamide

To a solution ofN-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-bromo-1,5-naphthyridine-2-carboxamide(20.0 mg, 0.0453 mmol),2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (fromCombi-Blocks, Catalogue Number: PN2659; 22.0 mg, 0.0916 mmol) in1,4-dioxane (1.0 mL) and water (0.3 mL) were added Cs₂CO₃ (30 mg, 0.091mmol) and(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(3.6 mg, 0.0045 mmol). The reaction mixture was stirred at 90° C. for 1h before it was diluted and purified by RP-HPLC (pH 10) to yield thetitle product (10.0 mg, 47%). LCMS calc. for C₂₆H₂₅F₂N₆O [M+H]⁺ m/z:475.1; found 475.1. ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (s, 1H), 9.24 (d,J=3.0 Hz, 1H), 8.77 (d, J=5.0 Hz, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.58(d, J=5.0 Hz, 1H), 8.28 (d, J=5.0 Hz, 1H), 7.65 (m, 1H), 7.35 (t, J=10.0Hz, 2H), 7.13 (d, J=5.0 Hz, 1H), 3.27 (m, 2H), 3.20 (d, J=15.0 Hz, 1H),3.10 (m, 1H), 3.09 (m, 1H), 2.32 (t, J=12.5 Hz, 1H), 2.23 (t, J=12.5 Hz,1H), 2.15 (m, 1H), 1.98 (d, J=12.5 Hz, 1H), 0.82 (d, J=5.0 Hz, 3H) ppm.

Example 2N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropyl-1,5-naphthyridine-2-carboxamide

To a solution ofN-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl})-7-bromo-1,5-naphthyridine-2-carboxamide(20.0 mg, 0.0453 mmol),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (fromSigma-Aldrich, Catalogue Number: 663212; 15.4 mg, 0.0916 mmol) in1,4-dioxane (1.0 mL) and water (0.3 mL) were added Cs₂CO₃ (30 mg, 0.091mmol) and (2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(3.6 mg, 0.0045 mmol). The reaction mixture was stirred at 90° C. for 1h before it was concentrated under reduced pressure. The mixture wasdissolved in MeOH (1 mL) and Pd on carbon (10% wt, 10 mg) was added. Thereaction mixture was stirred under a H₂ balloon for 2 h before it wasfiltered, diluted, and purified by RP-HPLC (pH 10). LCMS calc. forC₂₃H₂₉N₆O [M+H]⁺ m/z: 405.1; found 405.1.

Example 3N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)-1,5-naphthyridine-2-carboxamide

This compound was synthesized by the same method described in Example 2by using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(from Sigma-Aldrich, Catalogue Number: D10417) instead of2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS calc. forC₂₅H₃₁N₆O₂ [M+H]⁺ m/z: 447.1; found 447.1.

Example 4N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide

This compound was synthesized by the same method described in Example 1by using (2,6-difluoro-4-methoxyphenyl)boronic acid (from Sigma-Aldrich,Catalogue Number: 593060) instead of2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₇H₂₇F₂N₆O₂[M+H]⁺ m/z: 505.1; found 505.1.

Example 5N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide

This compound was synthesized by the same method described in Example 1by using 1-ethyl-1H-pyrazol-4-yl)boronic acid instead of2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₅H₂₉N₈O [M+H]⁺ m/z: 457.2; found 457.1.

Example 6N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropenyl-1,5-naphthyridine-2-carboxamide

This compound was synthesized by the same method described in Example 2by usingtert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamateinstead ofN-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-bromo-1,5-naphthyridine-2-carboxamide.LCMS calc. for C₂₃H₂₉N₆O₂ [M+H]⁺ m/z: 421.1; found 421.1. ¹H NMR (500MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.44 (s, 1H), 9.11 (d, J=3.0 Hz, 1H),8.66 (d, J=5.0 Hz, 1H), 8.45 (d, J=5.0 Hz, 1H), 8.28 (d, J=5.0 Hz, 1H),7.15 (d, J=5.0 Hz, 1H), 4.98 (d, J=5.0 Hz, 1H), 3.29 (m, 2H), 3.09 (m,1H), 2.81 (m, 1H), 2.57 (t, J=10.0 Hz, 1H), 2.49 (m, 5H), 2.16 (m, 1H),1.40 (s, 3H), 1.38 (s, 3H), 0.91 (d, J=10.0 Hz, 3H) ppm.

Example 7N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide

This compound was synthesized by the same method described in Example 6by using2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (fromSigma-Aldrich, Catalogue Number: 636029) instead of2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS calc. forC₂₆H₂₈N₇O₃ [M+H]⁺ m/z: 486.1; found 486.1.

Example 8N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-yl-1,5-naphthyridine-2-carboxamide

To a vial,N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-bromo-1,5-naphthyridine-2-carboxamide(30.0 mg, 0.0656 mmol), K₃PO₄ (70 mg, 0.33 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (34.9 mg, 0.0449 mmol), anddicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (26.2 mg, 0.0561mmol) were added. The vial was sealed with a PTFE screw-cap, evacuated,and backfilled with N₂ (this process was repeated a total of threetimes). A solution of morpholine (76.4 mg, 0.877 mmol) in anhydroust-BuOH (1.0 mL) was added via syringe. The reaction was heated at 100°C. After 2 h at 100° C., the reaction was complete. The product waspurified by RP-HPLC (pH=10). LCMS calc. for C₂₄H₃₀N₇O₃ [M+H]⁺ m/z:464.2; found 464.1.

Example 9N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide

Step 1. tert-Butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

To a mixture of 7-bromoquinoline-2-carboxylic acid (Aldrich, 158.1 mg,0.6272 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(281.0 mg, 0.6434 mmol) and HATU (715.0 mg, 1.88 mmol) was added DMF(4.0 mL) followed by DIPEA (407.9 mg, 3.156 mmol). After stirring atroom temperature for 3 h, the reaction was concentrated under reducedpressure. The residue was purified on silica gel (40 g, 0-100% EtOAc inhexanes) to give the sub-title product as a yellow solid (375.4 mg,89%). LCMS calc. for C₃₂H₄₅BrN₅O₄Si (M+H)⁺: m/z=670.2; found 670.3.

Step 2. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-{[(7-vinylquinolin-2-yl)carbonyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(287.6 mg, 0.4288 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (XPhos Pd G2, Aldrich, 34.2 mg, 0.0435 mmol), and K₃PO₄ (396.1 mg,1.866 mmol). The vial was sealed with a PTFE-lined septum, evacuated,and backfilled with N₂ (this process was repeated a total of threetimes). A solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(Aldrich, 198.4 mg, 1.288 mmol) in 1,4-dioxane (3.00 mL) was addedfollowed by deoxygenated water (1.00 mL). The reaction mixture wasstirred at 80° C. for 1 h. After cooling to room temperature, thereaction was filtered through a silica gel plug (eluted with EtOAc). Thefiltrate was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The resulting residue was purified on silica gel (40 g,0-100% EtOAc in hexanes) to give the sub-title product as a redsemi-solid (257.1 mg, 97%). LCMS calc. for C₃₄H₄₈N₅O₄Si (M+H)⁺:m/z=618.3; found 618.3.

Step 3.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide

To a solution of tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-{[(7-vinylquinolin-2-yl)carbonyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate(257.1 mg, 0.4161 mmol) in MeOH (3.00 mL) was added 10 wt % Pd on carbon(95.6 mg). The mixture was stirred at room temperature under H₂atmosphere (1 atm) for 15 h. The reaction was then filtered through apad of diatomaceous earth (eluted with MeOH), and concentrated. To theresulting residue was added 4.0 M HCl in dioxane (7.00 mL, 28.0 mmol).After stirring at room temperature for 3 h, the reaction mixture wasconcentrated. The residue was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.1% NH₄OH, atflow rate of 30 mL/min.) to afford the title product as a white solid(47.6 mg, 28%). LCMS calc. for C₂₃H₂₈N₅O₂ (M+H)⁺: m/z=406.2; found406.3.

Example 10N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide

Step 1. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(7-isopropenylquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(from Example 8, Step 1, 275.3 mg, 0.4104 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (XPhos Pd G2, Aldrich, 29.3 mg, 0.0372 mmol), and K₃PO₄ (380.0 mg,1.790 mmol). The vial was sealed with a PTFE-lined septum, evacuated,and backfilled with N₂ (this process was repeated a total of threetimes). A solution of2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (215.7 mg, 1.284mmol) in 1,4-dioxane (3.00 mL) was added, followed by deoxygenated water(1.00 mL). The reaction mixture was stirred at 80° C. for 1 h. Aftercooling to room temperature, the reaction was filtered through a pad ofdiatomaceous earth (eluted with EtOAc). The filtrate was washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The resultingresidue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) togive the sub-title product as a yellow foamy solid (206.1 mg, 79%). LCMScalc. for C₃₅H₅₀N₅O₄Si (M+H)⁺: m/z=632.4; found 632.4.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide

To a solution of tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(7-isopropenylquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(206.1 mg, 0.3262 mmol) in MeOH (3.00 mL) was added 10 wt % Pd on carbon(85.6 mg). The mixture was stirred at room temperature under H₂atmosphere (1 atm) for 15 h. The reaction was then filtered through apad of diatomaceous earth (eluted with MeOH), and concentrated. To theresulting residue was added 4.0 M HCl in dioxane (5.00 mL, 20.0 mmol).After stirring at room temperature for 3 h, the reaction mixture wasconcentrated. The residue was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.1% NH₄OH, atflow rate of 30 mL/min.) to afford the title product as a white solid(70.8 mg, 52%). LCMS calc. for C₂₄H₃₀N₅O₂ (M+H)⁺: m/z=420.2; found420.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.64 (s, 1H), 9.48 (s, 1H), 8.61 (d,J=8.4 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.05 (d,J=8.5 Hz, 1H), 8.00 (s, 1H), 7.70 (d, J=8.5, 1H), 7.15 (d, J=5.3 Hz,1H), 4.98 (d, J=4.8 Hz, 1H), 3.34-3.03 (m, 4H), 2.81 (m, 1H), 2.58 (t,J=11.0 Hz, 1H), 2.48 (t, J=11.0 Hz, 1H), 2.25-2.10 (m, 1H), 1.62 (br,2H), 1.35 (d, J=6.9 Hz, 6H), 0.92 (d, J=6.6 Hz, 3H) ppm.

Example 11N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide

Step 1. tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(from Example 8, Step 1, 190.5 mg, 0.2840 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(Aldrich, 118.0 mg, 0.5617 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (XPhos Pd G2, Aldrich, 26.7 mg, 0.0339 mmol), and K₃PO₄ (207.0 mg,0.9752 mmol). The vial was sealed with a PTFE-lined septum, evacuated,and backfilled with N₂ (this process was repeated a total of threetimes). 1,4-Dioxane (3.00 mL) was added, followed by deoxygenated water(1.00 mL). The reaction mixture was stirred at 80° C. for 1 h. Aftercooling to room temperature, the reaction was filtered through a pad ofdiatomaceous earth (eluted with EtOAc). The filtrate was washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The resultingresidue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) togive the sub-title product as a yellow foamy solid (123.2 mg, 64%). LCMScalc. for C₃₇H₅₂N₅O₅Si (M+H)⁺: m/z=674.4; found 674.3.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide

To a solution of tert-butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(123.2 mg, 0.1828 mmol) in MeOH (2.00 mL) was added 10 wt % Pd on carbon(48.8 mg). The mixture was stirred at room temperature under H₂atmosphere (1 atm.) for 15 h. The reaction mixture was then filteredthrough a pad of diatomaceous earth (eluted with MeOH), andconcentrated. To the resulting residue was added 4.0 M HCl in dioxane(5.00 mL, 20.0 mmol). After stirring at room temperature for 3 h, thereaction mixture was concentrated. The residue was purified usingRP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/watercontaining 0.1% NH₄OH, at flow rate of 30 mL/min.) to afford the titleproduct as a white solid (46.4 mg, 55%). LCMS calc. for C₂₆H₃₂N₅O₃(M+H)⁺: m/z=462.3; found 462.2.

Example 12N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide

Step 1. Methyl 7-bromoquinoline-2-carboxylate

To a mixture of 7-bromoquinoline-2-carboxylic acid (4.25 g, 16.9 mmol)and K₂CO₃ (3.54 g, 25.6 mmol) was added DMF (20.0 mL). The mixture wascooled to 0° C. Then a solution of MeI (2.89 g, 20.4 mmol) in DMF (11.0mL) was added slowly. The reaction mixture was allowed to warm to roomtemperature. After stirring at room temperature for 16 h, the reactionmixture was poured into water (150 mL) and extracted with EtOAc (3×100mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The resulting residue was purifiedon silica gel (120 g, 0-50% DCM in EtOAc) to give the sub-title productas a pale yellow solid (4.07 g, 91%). LCMS calc. for C₁₁H₉BrNO₂ (M+H)⁺:m/z=266.0; found 265.9.

Step 2. 7-Morpholin-4-ylquinoline-2-carboxylic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (438.2 mg, 1.647 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 112.0 mg, 0.1442 mmol), and Cs₂CO₃ (1.752g, 5.377 mmol). The vial was sealed with a PTFE-lined septum, evacuatedand backfilled with N₂ (this process was repeated a total of threetimes). A solution of morpholine (251.6 mg, 2.888 mmol) in anhydroust-BuOH (6.00 mL) was added via syringe. The mixture was heated to 100°C. for 10 h. After cooling to room temperature, the reaction mixture waspoured into brine (50 mL) and extracted with EtOAc (3×50 mL). Theaqueous layer was acidified to pH 4 with AcOH. Then it was extractedwith DCM (10×50 mL). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated to give the crude product as a yellow solid(405.1 mg) which was used directly in the next step without furtherpurification. LCMS calc. for C₁₄H₁₅N₂O₃ (M+H)⁺: m/z=259.1; found 259.1.

Step 3.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide

To a mixture of 7-morpholin-4-ylquinoline-2-carboxylic acid (70.0 mg,0.271 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(122.2 mg, 0.2798 mmol) and HATU (318.5 mg, 0.8376 mmol) was added DMF(2.50 mL) followed by DIPEA (198.5 mg, 1.536 mmol). After stirring atroom temperature for 1 h, the reaction was concentrated under reducedpressure. The residue was purified on silica gel (40 g, 0-100% EtOAc inhexanes) to give a brown semi-oil. To this brown semi-oil was added 4.0M HCl in dioxane (4.00 mL, 16.0 mmol). The mixture was stirred at roomtemperature for 2 h, and then concentrated. The residue was purifiedusing RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (45.1 mg, 36%). LCMS calc. forC₂₅H₃₁N₆O₃ (M+H)⁺: m/z=463.2; found 463.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.79 (s, 1H), 9.53 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.26 (d, J=5.3 Hz,1H), 8.02 (d, J=8.2 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.63 (dd, J=9.2,2.3 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 5.06 (d,J=4.3 Hz, 1H), 3.82-3.78 (m, 4H), 3.38 (m, 4H), 3.23 (m, 1H), 3.19-3.10(m, 2H), 2.83 (m, 1H), 2.58 (t, J=10.9 Hz, 1H), 2.49 (m, 1H), 2.30-2.14(m, 1H), 1.63 (br, 2H), 0.93 (d, J=6.6 Hz, 3H) ppm.

Example 13N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide

To a mixture of 7-morpholin-4-ylquinoline-2-carboxylic acid (70.0 mg,0.271 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (84.6mg, 0.276 mmol) and HATU (315.0 mg, 0.8284 mmol) was added DMF (2.50 mL)followed by DIPEA (195.4 mg, 1.512 mmol). After stirring at roomtemperature for 1 h, the reaction was concentrated under reducedpressure. The residue was purified on silica gel (40 g, 5% MeOH in DCM)to give a brown semi-oil. To this brown semi-oil was added DCM (2.00mL), and TFA (2.00 mL). The mixture was stirred at room temperature for2 h, and then concentrated. The residue was purified using RP-HPLC(XBridge™ C18 column, eluting with a gradient of MeCN/water containing0.1% NH₄OH, at flow rate of 30 mL/min.) to afford the title product as ayellow solid (33.2 mg, 27%). LCMS calc. for C₂₅H₃₁N₆O₂ (M+H)⁺:m/z=447.3; found 447.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.66 (s, 1H), 9.47(s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H), 8.03 (d, J=8.2Hz, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.65 (dd, J=9.1, 2.2 Hz, 1H), 7.26 (d,J=2.2 Hz, 1H), 7.15 (d, J=5.3 Hz, 1H), 3.83 (m, 4H), 3.36 (m, 4H),3.33-3.13 (m, 3H), 2.29 (m, 2H), 2.25-2.14 (m, 1H), 2.03 (m, 1H), 1.60(br, 2H), 0.88 (m, 4H) ppm.

Example 14N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide

Step 1. 7-(3-Oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxylic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (256.2 mg, 0.9628 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 72.9 mg, 0.0939 mmol), and Cs₂CO₃ (1.005g, 3.084 mmol). The vial was sealed with a PTFE-lined septum, evacuatedand backfilled with N₂ (this process was repeated a total of threetimes). A solution of 3-oxa-9-azaspiro[5.5]undecane (273.0 mg, 1.758mmol) in anhydrous t-BuOH (4.00 mL) was added via syringe. The mixturewas heated to 100° C. for 10 h. After cooling to room temperature, thereaction mixture was poured into brine (50 mL) and extracted with EtOAc(3×50 mL). The aqueous layer was acidified to pH 4 with AcOH. Then itwas extracted with DCM (10×50 mL). The combined organic layer was driedover Na₂SO₄, filtered, and concentrated to give the crude product as ayellow solid (310.6 mg) which was used directly in the next step withoutfurther purification. LCMS calc. for C₁₉H₂₃N₂O₃ (M+H)⁺: m/z=327.2; found327.1.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide

To a mixture of7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxylic acid (95.5 mg,0.292 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(139.2 mg, 0.3188 mmol) and HATU (361.6 mg, 0.9510 mmol) was added DMF(2.00 mL) followed by DIPEA (300.0 μL, 1.722 mmol). After stirring atroom temperature for 2 h, the reaction was concentrated under reducedpressure. The residue was purified on silica gel (40 g, 0-100% EtOAc inhexanes) to give a brown semi-oil. To this brown semi-oil was added 4.0M HCl in dioxane (4.00 mL, 16.0 mmol). The mixture was stirred at roomtemperature for 2 h, and was then concentrated under reduced pressure.The residue was purified using RP-HPLC (XBridge™ C18 column, elutingwith a gradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title product as a yellow solid (62.1 mg, 40%).LCMS calc. for C₃₀H₃₉N₆O₃ (M+H)⁺: m/z=531.3; found 531.3. ¹H NMR (500MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.53 (s, 1H), 8.39 (d, J=8.2 Hz, 1H),8.25 (d, J=5.2 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H),7.60 (dd, J=9.2, 2.5 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.15 (d, J=5.3 Hz,1H), 5.06 (s, 1H), 3.64-3.54 (m, 4H), 3.49-3.41 (m, 4H), 3.25-3.20 (m,1H), 3.20-3.14 (m, 1H), 3.14-3.07 (m, 1H), 2.83 (m, 1H), 2.58 (t, J=10.9Hz, 1H), 2.49 (m, 1H), 2.28-2.13 (m, 1H), 1.70-1.56 (m, 6H), 1.53-1.43(m, 4H), 0.93 (d, J=6.6 Hz, 3H) ppm.

Example 15N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide

To a mixture of7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxylic acid (96.8 mg,0.296 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (103.4mg, 0.3375 mmol) and HATU (351.6 mg, 0.9247 mmol) was added DMF (2.00mL) followed by DIPEA (300.0 μL, 1.722 mmol). After stirring at roomtemperature for 2 h, the reaction was diluted with EtOAc. The mixturewas washed with water, and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. To the resulting residue was addedDCM (2.00 mL) and TFA (2.00 mL). The reaction mixture was stirred atroom temperature for 2 h, and then concentrated. The residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (62.4 mg, 41%). LCMS calc. forC₃₀H₃₉N₆O₂ (M+H)⁺: m/z=515.3; found 515.3.

Example 16N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide

Step 1. 7-(4-Cyanopiperidin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (240.4 mg, 0.9034 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 81.7 mg, 0.1052 mmol), and Cs₂CO₃ (893.0mg, 2.741 mmol). The vial was sealed with a PTFE-lined septum, evacuatedand backfilled with N₂ (this process was repeated a total of threetimes). A solution of piperidine-4-carbonitrile (181.0 mg, 1.643 mmol)in anhydrous t-BuOH (6.00 mL) was added via syringe. The mixture washeated to 100° C. for 10 h. After cooling to room temperature, thereaction mixture was diluted with MeOH (20 mL). AcOH (1.00 mL, 17.6mmol) was added. The mixture was filtered through a pad of diatomaceousearth (eluted with MeOH). The filtrate was concentrated under reducedpressure, and the residue was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.05% TFA, atflow rate of 30 mL/min.) to afford the title product as a red solid(126.4 mg, 35%). LCMS calc. for C₁₆H₁₆N₃O₂ (M+H)⁺: m/z=282.1; found282.1.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-cyanopiperidin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid (62.5 mg, 0.158 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(91.4 mg, 0.209 mmol) and HATU (219.1 mg, 0.5762 mmol) was added DMF(2.00 mL) followed by DIPEA (180.0 mg, 1.393 mmol). After stirring atroom temperature for 18 h, the reaction was diluted with EtOAc. Themixture was washed with water and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. To the resulting residue wasadded 4.0 M HCl in dioxane (4.00 mL, 16.0 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then concentrated. Theresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title product as a yellow solid (42.8 mg, 56%).LCMS calc. for C₂₇H₃₂N₇O₂ (M+H)⁺: m/z=486.3; found 486.3.

Example 17N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-cyanopiperidin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid (57.3 mg, 0.145 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (55.1mg, 0.180 mmol) and HATU (196.1 mg, 0.5157 mmol) was added DMF (2.00 mL)followed by DIPEA (163.8 mg, 1.267 mmol). After stirring at roomtemperature for 18 h, the reaction mixture was diluted with EtOAc. Themixture was washed with water and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. To the resulting residue wasadded DCM (2.00 mL) and TFA (2.00 mL). The reaction mixture was stirredat room temperature for 2 h, and then concentrated. The residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (41.9 mg, 62%). LCMS calc. forC₂₇H₃₂N₇O (M+H)⁺: m/z=470.3; found 470.2.

Example 18N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide

Step 1. 7-(4-Methylpiperazin-1-yl)quinoline-2-carboxylic acid[1.0]-trifitioroacetic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (158.7 mg, 0.5964 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 52.9 mg, 0.0681 mmol), and Cs₂CO₃ (602.4mg, 1.849 mmol). The vial was sealed with a PTFE-lined septum,evacuated, and backfilled with N₂ (this process was repeated a total ofthree times). A solution of 1-methylpiperazine (125.7 mg, 1.255 mmol) inanhydrous t-BuOH (4.00 mL) was added via syringe. The mixture was heatedto 100° C. for 10 h. After cooling to room temperature, the reactionmixture was diluted with MeOH (20 mL). AcOH (1.00 mL, 17.6 mmol) wasadded. The mixture was filtered through a pad of diatomaceous earth(eluted with MeOH). The filtrate was concentrated under reducedpressure, and the residue was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.05% TFA, atflow rate of 30 mL/min.) to afford the title product as a red solid(180.2 mg, 78%). LCMS calc. for C₁₅H₁₈N₃O₂ (M+H)⁺: m/z=272.1; found272.1.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid (90.3 mg, 0.234 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(94.6 mg, 0.217 mmol) and HATU (258.1 mg, 0.6788 mmol) was added DMF(2.00 mL) followed by DIPEA (237.3 mg, 1.836 mmol). After stirring atroom temperature for 18 h, the reaction was diluted with EtOAc. Themixture was washed with water, and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. To the resulting residue wasadded 0.4.0 M HCl in dioxane (4.00 mL, 16.0 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then concentrated. Theresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title product as a yellow solid (22.7 mg, 22%).LCMS calc. for C₂₆H₃₄N₇O₂ (M+H)⁺: m/z=476.3; found 476.3.

Example 19N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid (78.4 mg, 0.203 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (53.7mg, 0.175 mmol) and HATU (238.7 mg, 0.6278 mmol) was added DMF (2.00 mL)followed by DIPEA (196.1 mg, 1.517 mmol). After stirring at roomtemperature for 18 h, the reaction was diluted with EtOAc. The mixturewas washed with water, and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. To the resulting residue was addedDCM (2.00 mL) and TFA (2.00 mL). The reaction mixture was stirred atroom temperature for 2 h, and then concentrated. The residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (24.9 mg, 31%). LCMS calc. forC₂₆H₃₄N₇O (M+H)⁺: m/z=460.3; found 460.3.

Example 20N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide

Step 1. 7-(4-Pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (245.1 mg, 0.9211 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 74.5 mg, 0.0959 mmol),4-piperidin-4-ylpyridine [1.0]-HCl (340.8 mg, 1.715 mmol), and Cs₂CO₃(1.811 g, 5.558 mmol). The vial was sealed with a PTFE-lined septum,evacuated, and backfilled with N₂ (this process was repeated a total ofthree times). Anhydrous t-BuOH (6.00 mL) was added via syringe. Themixture was heated at 100° C. for 10 h. After cooling to roomtemperature, the reaction mixture was diluted with MeOH (20 mL). AcOH(1.00 mL, 17.6 mmol) was added. The mixture was filtered through a padof diatomaceous earth (eluted with MeOH). The filtrate was concentratedunder reduced pressure, and the residue was purified using RP-HPLC(XBridge™ C18 column, eluting with a gradient of MeCN/water containing0.05% TFA, at flow rate of 30 mL/min.) to afford the title product as ared solid (184.8 mg, 45%). LCMS calc. for C₂₀H₂₀N₃O₂ (M+H)⁺: m/z=334.2;found 334.1.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxylicacid [1.0]-trifluoroacetic acid (103.6 mg, 0.2316 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(96.7 mg, 0.221 mmol) and HATU (269.6 mg, 0.7090 mmol) was added DMF(2.00 mL) followed by DIPEA (256.0 mg, 1.981 mmol).) After stirring atroom temperature for 18 h, the reaction was diluted with EtOAc. Themixture was washed with water, and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. To the resulting residue wasadded 4.0 M HCl in dioxane (4.00 mL, 16.0 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then concentrated. Theresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title product as a yellow solid (49.4 mg, 42%).LCMS calc. for C₃₁H₃₆N₇O₂ (M+H)⁺: m/z=538.3; found 538.3.

Example 21N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxylicacid [1.0]-trifluoroacetic acid (83.1 mg, 0.186 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (53.0mg, 0.173 mmol) and HATU (221.0 mg, 0.5812 mmol) was added DMF (2.00 mL)followed by DIPEA (195.8 mg, 1.515 mmol). After stirring at roomtemperature for 18 h, the reaction was diluted with EtOAc. The mixturewas washed with water, and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. To the resulting residue was addedDCM (2.00 mL) and TFA (2.00 mL). The reaction mixture was stirred atroom temperature for 2 h, and then concentrated. The residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (41.4 mg, 46%). LCMS calc. forC₃₁H₃₆N₇O (M+H)⁺: m/z=522.3; found 522.3.

Example 22N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide

Step 1. 7-(4-Ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (152.9 mg, 0.5746 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 56.1 mg, 0.0722 mmol), and Cs₂CO₃ (595.5mg, 1.828 mmol). The vial was sealed with a PTFE-lined septum, evacuatedand backfilled with N₂ (this process was repeated a total of threetimes). A solution of 1-ethylpiperazin-2-one (153.2 mg, 1.195 mmol) inanhydrous t-BuOH (4.00 mL) was added via syringe. The mixture was heatedto 100° C. for 10 h. After cooling to room temperature, the reactionmixture was diluted with MeOH (20 mL). AcOH (1.00 mL, 17.6 mmol) wasadded. The mixture was filtered through a pad of diatomaceous earth(eluted with MeOH). The filtrate was concentrated under reducedpressure, and the residue was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.05% TFA, atflow rate of 30 mL/min.) to afford the title product as a red solid(117.3 mg, 49%). LCMS calc. for C₁₆H₁₈N₃O₃ (M+H)⁺: m/z=300.1; found300.1.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxylicacid [1.0]-trifluoroacetic acid (56.6 mg, 0.137 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(57.7 mg, 0.132 mmol) and HATU (166.8 mg, 0.4387 mmol) was added DMF(2.00 mL) followed by DIPEA (160.1 mg, 1.239 mmol). After stirring atroom temperature for 18 h, the reaction was diluted with EtOAc. Themixture was washed with water, and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. To the resulting residue wasadded 0.4.0 M HCl in dioxane (4.00 mL, 16.0 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then concentrated. Theresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title product as a yellow solid (40.5 mg, 61%).LCMS calc. for C₂₇H₃₄N₇O₃ (M+H)⁺: m/z=504.3; found 504.3.

Example 23N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxylicacid [1.0]-trifluoroacetic acid (60.8 mg, 0.147 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (44.1mg, 0.144 mmol) and HATU (176.7 mg, 0.4647 mmol) was added DMF (2.00 mL)followed by DIPEA (163.2 mg, 1.263 mmol). After stirring at roomtemperature for 18 h, the reaction was diluted with EtOAc. The mixturewas washed with water, and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. To the resulting residue was addedDCM (2.00 mL) and TFA (2.00 mL). The reaction mixture was stirred atroom temperature for 2 h, and then concentrated. The residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (43.4 mg, 62%). LCMS calc. forC₂₇H₃₄N₇O₂ (M+H)⁺: m/z=488.3; found 488.3.

Example 24N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide

Step 1. 7-(4-Methoxypiperidin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (151.9 mg, 0.5708 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 57.4 mg, 0.0739 mmol), and Cs₂CO₃ (598.9mg, 1.838 mmol). The vial was sealed with a PTFE-lined septum, evacuatedand backfilled with N₂ (this process was repeated a total of threetimes). A solution of 4-methoxypiperidine (148.4 mg, 1.288 mmol) inanhydrous t-BuOH (4.00 mL) was added via syringe. The mixture was heatedto 100° C. for 10 h. After cooling to room temperature, the reactionmixture was diluted with MeOH (20 mL). AcOH (1.00 mL, 17.6 mmol) wasadded. The mixture was filtered through a pad of diatomaceous earth(eluted with MeOH). The filtrate was concentrated under reducedpressure, and the residue was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.05% TFA, atflow rate of 30 mL/min.) to afford the title product as a red solid(77.4 mg, 34%). LCMS calc. for C₁₆H₁₉N₂O₃ (M+H)⁺: m/z=287.1; found287.1.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-methoxypiperidin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid (37.8 mg, 0.0944 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(42.4 mg, 0.0971 mmol) and HATU (120.3 mg, 0.3164 mmol) was added DMF(2.00 mL) followed by DIPEA (117.9 mg, 0.9122 mmol). After stirring atroom temperature for 18 h, the reaction was diluted with EtOAc. Themixture was washed with water, and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. To the resulting residue wasadded 4.0 M HCl in dioxane (4.00 mL, 16.0 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then concentrated. Theresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title product as a yellow solid (26.7 mg, 58%).LCMS calc. for C₂₇H₃₅N₆O₃ (M+H)⁺: m/z=491.3; found 491.3.

Example 25N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-methoxypiperidin-1-yl)quinoline-2-carboxylic acid[1.0]-trifluoroacetic acid (41.2 mg, 0.103 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (32.5mg, 0.106 mmol) and HATU (132.2 mg, 0.3477 mmol) was added DMF (2.00 mL)followed by DIPEA (140.2 mg, 1.085 mmol). After stirring at roomtemperature for 18 h, the reaction was diluted with EtOAc. The mixturewas washed with water, and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. To the resulting residue was addedDCM (2.00 mL) and TFA (2.00 mL). The reaction mixture was stirred atroom temperature for 2 h, and then concentrated. The residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (26.2 mg, 54%). LCMS calc. forC₂₇H₃₅N₆O₂ (M+H)⁺: m/z=475.3; found 475.2.

Example 26N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide

Step 1. 7-(4-Morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxylic acid[1. 0]-trifluoroacetic acid

To a screw-cap vial equipped with a magnetic stir bar was added methyl7-bromoquinoline-2-carboxylate (154.9 mg, 0.5821 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (RuPhos Pd G2, Aldrich, 57.1 mg, 0.0735 mmol), and Cs₂CO₃ (623.3mg, 1.913 mmol). The vial was sealed with a PTFE-lined septum, evacuatedand backfilled with N₂ (this process was repeated a total of threetimes). A solution of 4-piperidin-4-ylmorpholine (215.7 mg, 1.267 mmol)in anhydrous t-BuOH (4.00 mL) was added via syringe. The mixture washeated to 100° C. for 10 h. After cooling to room temperature, thereaction mixture was diluted with MeOH (20 mL). AcOH (1.00 mL, 17.6mmol) was added. The mixture was filtered through a pad of diatomaceousearth (eluted with MeOH). The filtrate was concentrated under reducedpressure, and the residue was purified using RP-HPLC (XBridge™ C18column, eluting with a gradient of MeCN/water containing 0.05% TFA, atflow rate of 30 mL/min.) to afford the title product as a red solid(147.0 mg, 55%). LCMS calc. for C₁₉H₂₄N₃O₃ (M+H)⁺: m/z=342.2; found342.2.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxylicacid [1.0]-trifluoroacetic acid (74.9 mg, 0.164 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(73.3 mg, 0.168 mmol) and HATU (206.9 mg, 0.5441 mmol) was added DMF(2.00 mL) followed by DIPEA (230.7 mg, 1.785 mmol). After stirring atroom temperature for 18 h, the reaction was diluted with EtOAc. Themixture was washed with water, and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. To the resulting residue wasadded 4.0 M HCl in dioxane (4.00 mL, 16.0 mmol). The reaction mixturewas stirred at room temperature for 2 h, and then concentrated. Theresidue was purified using RP-HPLC (XBridge™ C18 column, eluting with agradient of MeCN/water containing 0.1% NH₄OH, at flow rate of 30mL/min.) to afford the title product as a yellow solid (35.6 mg, 40%).LCMS calc. for C₃₀H₄₀N₇O₃ (M+H)⁺: m/z=546.3; found 546.3.

Example 27N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide

To a mixture of 7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxylicacid [1.0]-trifluoroacetic acid (73.9 mg, 0.162 mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (49.8mg, 0.162 mmol) and HATU (197.2 mg, 0.5186 mmol) was added DMF (2.00 mL)followed by DIPEA (226.0 mg, 1.749 mmol). After stirring at roomtemperature for 18 h, the reaction was diluted with EtOAc. The mixturewas washed with water, and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. To the resulting residue was addedDCM (2.00 mL) and TFA (2.00 mL). The reaction mixture was stirred atroom temperature for 2 h, and then concentrated. The residue waspurified using RP-HPLC (XBridge™ C18 column, eluting with a gradient ofMeCN/water containing 0.1% NH₄OH, at flow rate of 30 mL/min.) to affordthe title product as a yellow solid (34.3 mg, 40%). LCMS calc. forC₃₀H₄₀N₇O₂ (M+H)⁺: m/z=530.3; found 530.3.

Example 28N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide

Step 1: 7-[3-(Trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxylicacid

A mixture of methyl 7-bromoquinoline-2-carboxylate (40.0 mg, 0.15 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (23.4 mg, 0.03 mmol) and Cs₂CO₃ (0.17 g, 0.53 mmol) in a sealedtube was evacuated and backfilled with N₂. A solution of3-(trifluoromethyl)pyrrolidine HCl (47.5 mg, 0.27 mmol) in anhydroust-BuOH (0.62 mL) was then added. The resulting reaction mixture washeated to 100° C. and stirred for 16 h. The reaction mixture was cooledto room temperature, neutralized with 4M HCl and diluted with EtOAc. Theaqueous layer was extracted with EtOAc (2×) to remove impurities. Thesolvents and water were removed under reduced pressure. The residue wasdiluted with THF, dried, filtered and concentrated under reducedpressure to give the yellow solid (70 mg, 95%). LCMS calc. forC₁₅H₁₄F₃N₂O₂ (M+H)⁺: m/z=311.3. Found: 311.3.

Step 2: tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-{3-[({7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinolin-2-yl}carbonyl)amino]pyridin-4-yl}piperidin-3-yl)carbamate

To a mixture of7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxylic acid (10.0mg, 0.032 mmol), tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(16.9 mg, 0.039 mmol) and HATU (36.8 mg, 0.097 mmol) was added DMF (0.20mL), followed by DIPEA (16.8 μL, 0.097 mmol). The reaction mixture wasstirred at room temperature for 20 h. The cloudy mixture was dilutedwith THF, filtered, and concentrated to give the crude intermediate,which was purified by preparative LCMS (pH=10 method; XBridge™ PrepC18 5m OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN andwater with NH₄OH) to give the sub-title product as light yellow powder(4 mg, 17%). LCMS calc. for C₃₇H₅₂F₃N₆O₄Si (M+H)⁺: m/z=729.3. Found:729.3.

Step 3:N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide

A solution of tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-{3-[({7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinolin-2-yl}carbonyl)amino]pyridin-4-yl}piperidin-3-yl)carbamatein 4.0 M HCl in dioxane (0.48 mL, 1.9 mmol) was stirred at roomtemperature for 60 min. The reaction mixture was concentrated underreduced pressure. The residue was purified on preparative LCMS (pH=10method; XBridge™ preparative C18 5 m OBD™ column, 30×10 mm, 60 mL/min.,eluting with a gradient of MeCN and water with NH₄OH) to give thesub-title product as yellow powder (1.0 mg, 6%). LCMS calc. forC₂₆H₃₀F₃N₆O₂ (M+H)⁺: m/z=515.2. Found: 515.3.

Example 29N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide

The title compound was prepared according to the procedure Example 28,using the following two starting materials,7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxylic acid (10.0mg, 0.032 mmol) (prepared in Example 27, step 1) and tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (11.8mg, 0.039 mmol), to afford the title product as a light yellow powder in8% yield (3 steps). LCMS calc. for C₂₆H₃₀F₃N₆O (M+H)⁺: m/z=499.2. Found:499.3.

Example 30N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide

Step 1: 7-Pyrrolidin-1-ylquinoline-2-carboxylic acid

A mixture of methyl 7-bromoquinoline-2-carboxylate (40.0 mg, 0.15 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (23.4 mg, 0.03 mmol) and Cs₂CO₃ (0.17 g, 0.53 mmol) in a sealedtube was evacuated and backfilled with N₂. A solution of pyrrolidine(19.2 mg, 0.27 mmol) in anhydrous t-BuOH (0.62 mL) was then added. Thereaction mixture was heated to 100° C. and stirred for 16 h. Thereaction mixture was cooled to room temperature, neutralized with 4 MHCl and diluted with EtOAc. The aqueous layer was extracted with EtOAc(2×) to remove impurities. The solvents and water were removed underreduced pressure. The residue was diluted with THF, dried, filtered, andconcentrated under reduced pressure to give the sub-title compound as ayellow solid (31 mg, 86%). LCMS calc. for C₁₄H₁₅N₂O₂ (M+H)⁺: m/z=243.1.Found: 243.2.

Step 2:N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide

The title compound was prepared according to the procedure Example 28,using the following two starting materials,7-pyrrolidin-1-ylquinoline-2-carboxylic acid (10.0 mg, 0.04 mmol) andtert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(21.6 mg, 0.050 mmol), to give the title product as yellow powder (3.7mg, 21%). LCMS calc. for C₂₅H₃₁N₆O₂ (M+H)⁺: m/z=447.2. Found: 447.3.

Example 31N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide

The title compound was prepared according to the procedure Example 28,using the following two starting materials,7-pyrrolidin-1-ylquinoline-2-carboxylic acid (10.0 mg, 0.041 mmol) andtert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (15.2mg, 0.050 mmol), to afford the title product as light yellow powder in13% yield (3 steps). LCMS calc. for C₂₅H₃₁N₆O (M+H)⁺: m/z=431.3. Found:431.2.

Example 32N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide

Step 1: 7-(3, 3-Dimethylazetidin-1-yl)quinoline-2-carboxylic acid

A mixture of methyl 7-bromoquinoline-2-carboxylate (40.0 mg, 0.15 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (23.4 mg, 0.03 mmol) and Cs₂CO₃ (0.17 g, 0.53 mmol) in a sealedtube was evacuated and backfilled with N₂. A solution of3,3-dimethylazetidine HCl (32.9 mg, 0.27 mmol) in anhydrous t-BuOH (0.62mL) was added. The resulting reaction mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperature,neutralized with 4M HCl and diluted with EtOAc. The aqueous layer wasextracted with EtOAc (2×) to remove impurities. The solvents and waterwere removed under reduced pressure. The crude was purified bypreparative LCMS (pH=2 method; Waters SunFire™ preparative C18 5 μm OBD™column, 30×100 mm, 60 mL/min., eluting with a gradient of MeCN and waterwith TFA) to give the sub-title compound as a yellow powder (24.7 mg,64%). LCMS calc. for C₁₅H₁₇N₂O₂ (M+H)⁺: m/z=257.1. Found: 257.3.

Step 2:N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide

The title compound was prepared according to the procedure Example 27,using the following two starting materials,7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxylic acid (8.0 mg, 0.03mmol) and tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(16.4 mg, 0.04 mmol), to afford the title product as light yellow powder(2.2 mg, 15%) in two steps. LCMS calc. for C₂₆H₃₃N₆O₂ (M+H)⁺: m/z=461.3.Found: 461.3.

Example 33N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide

The title compound was prepared according to the procedure Example 28,using the following two starting materials,7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxylic acid (8.0 mg, 0.03mmol) and tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (11.5mg, 0.037 mmol), to afford the title product as light yellow powder in17% yield (3 steps). LCMS calc. for C₂₆H₃₃N₆O (M+H)⁺: m/z=445.3. Found:445.3.

Example 34N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-azetidin-1-ylquinoline-2-carboxamide

Step 1: 7-Azetidin-1-ylquinoline-2-carboxylic acid

A mixture of methyl 7-bromoquinoline-2-carboxylate (40.0 mg, 0.15 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (23.4 mg, 0.030 mmol) and Cs₂CO₃ (0.17 g, 0.53 mmol) in a sealedtube was evacuated and backfilled with N₂. A solution of azetidinehydrochloride (25.3 mg, 0.27 mmol) in anhydrous t-BuOH (0.62 mL) wasadded. The resulting reaction mixture was heated to 100° C. and stirredfor 16 h. The reaction mixture was cooled to room temperature,neutralized with 4M HCl and diluted with EtOAc. The aqueous layer wasextracted with EtOAc (2×) to remove impurities. The solvents and waterwere removed under reduced pressure. The residue was diluted with THF,dried, filtered and concentrated to give the sub-title compound as ayellow solid (30 mg, 91%). LCMS calc. for C₁₃H₁₃N₂O₂ (M+H)⁺: m/z=229.1.Found: 229.2.

Step 2:N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-azetidin-1-ylquinoline-2-carboxamide

The title compound was prepared according to the procedure Example 28,using the following two starting materials,7-azetidin-1-ylquinoline-2-carboxylic acid (5.0 mg, 0.02 mmol) andtert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (8.1mg, 0.026 mmol) to give the title product as a yellow powder (2 mg,22%). LCMS calc. for C₂₄H₂₉N₆O (M+H)⁺: m/z=417.2. Found: 417.3.

Example 35N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide

Step 1: tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropyl-1-[3-({[7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridin-2-yl]carbonyl}amino)pyridin-4-yl]piperidin-3-yl}carbamate

A mixture of2-(2,6-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.036 g, 0.13 mmol), tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(0.068 g, 0.10 mmol), DIPEA (23 mg, 0.18 mmol), 1,4-dioxane (0.34 mL)and water (0.007 mL) was flushed with N₂ and thenbis(tri-t-butylphosphine)palladium (0.01 g, 0.02 mmol) was added. Thereaction mixture was sealed and heated at 120° C. for 2 h. Aftercooling, the reaction mixture was concentrated under reduced pressureand the crude was purified by preparative LC MS (pH=10 method; XBridge™preparative C18 5 m OBD™ column, 30×10 mm, 60 mL/min., eluting with agradient of MeCN and water with NH₄OH) to give the sub-title product asan off-white powder (62 mg, 84%). LCMS calc. for C₄₀H₅₁F₂N₆O₅Si (M+H)⁺:m/z=761.4. Found: 761.3.

Step 2:N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide

To a solution of tert-butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropyl-1-[3-({[7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridin-2-yl]carbonyl}amino)pyridin-4-yl]piperidin-3-yl}carbamate(62 mg, 0.08 mmol) in MeOH (2 mL) was added 4.0 M HCl in dioxane (2.0mL, 8.0 mmol). The reaction mixture was stirred at room temperature for30 min. After concentration under reduced pressure, the residue wasdiluted with MeOH and NH₄OH, filtered and purified by preparative LCMS(pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60mL/min., eluting with a gradient of MeCN and water with NH₄OH) to givethe title product as a white powder (38 mg, 71%). LCMS calc. forC₂₉H₂₉F₂N₆O₃ (M+H)⁺: m/z=547.2. Found: 547.3. ¹H NMR (500 MHz, DMSO-d₆):δ 10.34 (s, 1H), 9.34 (s, 1H), 9.18 (d, J=1.5, 1H), 8.75 (m, 1H), 8.58(m, 2H), 8.28 (d, J=5.3, 1H), 7.14 (d, J=5.4, 1H), 7.01 (d, J=10.1, 2H),4.60 (d, J=6.0, 1H), 3.89 (s, 3H), 3.27 (m, 2H), 2.96 (m, 2H), 2.59 (t,J=10.8, 1H), 2.55-2.49 (m, 1H), 1.66 (s, 2H), 1.25 (m, 1H), 0.57 (m,1H), 0.30 (m, 1H), 0.17 (m, 1H), 0.04 (m, 2H) ppm.

Example 36N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure Example 35,using the following two starting materials,(6-methoxypyridin-3-yl)boronic acid (6.0 mg, 0.039 mmol) and tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(0.020 g, 0.029 mmol), to afford the title product as a white powder.LCMS calc. for C₂₈H₃₀N₇O₃ (M+H)⁺: m/z=512.2. Found: 512.2.

Example 37N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)-1,5-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure Example 35,using the following two starting materials,4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine(110 mg, 0.039 mmol) and tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(20 mg, 0.029 mmol), to afford the title product as an off-white powder.LCMS calc. for C₃₁H₃₅N₈O₃ (M+H)⁺: m/z=567.3. Found: 567.3.

Example 38N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure Example 35,using the following two starting materials,1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.7mg, 0.039 mmol) and tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(20.0 mg, 0.029 mmol), to afford the title product as a white powder.LCMS calc. for C₂₇H₃₁N₈O₂ (M+H)⁺: m/z=499.3. Found: 499.3.

Example 39N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure Example 35,using the following two starting materials,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.1 mg, 0.039 mmol), and tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(20.0 mg, 0.029 mmol), to afford the title product as a white powder.LCMS calc. for C₂₆H₂₉N₈O₂ (M+H)⁺: m/z=485.3. Found: 485.3.

Example 40N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-1,5-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure Example 35,using the following two starting materials, tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(12 mg, 0.017 mmol) and 3-oxa-9-azaspiro[5.5]undecane (50 mg, 0.32mmol), to afford the title product as a yellow powder. LCMS calc. forC₃₁H₄₀N₇O₃ (M+H)⁺: m/z=558.3. Found: 558.4.

Example 41N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)-1,5-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure Example 35,using the following two starting materials, tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(12 mg, 0.017 mmol) and piperidine-4-carbonitrile (12 mg, 0.11 mmol), toafford the title product as a yellow powder. LCMS calc. for C₂₈H₃₃N₈O₂(M+H)⁺: m/z=513.3. Found: 513.2.

Example 42N-{4-[(3R,4R,5S)-3-Amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-1,5-naphthyridine-2-carboxamide

The title compound was prepared according to the procedure Example 35,using the following two starting materials, tert-butyl((3R,4R,5S)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-cyclopropylpiperidin-3-yl)carbamate(12 mg, 0.017 mmol) and 1-oxa-8-azaspiro[4.5]decane (46 mg, 0.32 mmol),to afford the title product as a yellow powder. LCMS calc. forC₃₀H₃₈N₇O₃ (M+H)⁺: m/z=544.3. Found: 544.4.

Example 43N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide

Step 1. tert-Butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A mixture of tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(1.7 g, 0.39 mmol), 7-bromoquinoline-2-carboxylic acid (1.0 g, 4.0 mmol)and N,N-diisopropylethylamine (1.4 mL, 8.0 mmol), and molecular sievesin 1,2-dichloroethane (60 mL) was stirred at room temperature for 0.5 h.Then HATU (0.031 g, 0.082 mmol) was added. The mixture was stirred atroom temperature overnight, diluted with 50 mL EtOAc, filtered through adiatomaceous earth funnel, washed with saturated NaHCO₃, water, andbrine. After separation of layers, the organic layers were dried overNa₂SO₄, and concentrated. The mixture was purified on 40 g silica gelcolumn using CombiFlash® apparatus eluting with EtOAc/hexane (10-100%)to give product as brown solid (2.20 g, 85%), LCMS calc. forC₃₂H₄₅BrN₅O₄Si (M+H)⁺: m/z=670.2. Found: 670.2.

Step 2.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide

In a microwave tube, a mixture of tert-butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(100 mg, 15 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (24 mg, 0.19mmol), and DIPEA (0.078 mL, 0.45 mmol) in 1,4-dioxane (4.1 mL) and water(0.40 mL) was purged with N₂ bubbles for 5 min. beforebis(tri-t-butylphosphine)palladium (20 mg, 0.04 mmol) was added. Thereaction mixture was then heated at 110° C. for 1 h. The crude mixturewas diluted with EtOAc and washed with saturated NaHCO₃ solution andbrine. The organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography (40 g column,20-100% EtOAc in hexanes) to give the coupling product.

The above coupling product was dissolved in small amount of MeOH and 4 NHCl was added. The mixture was stirred for 1 h at room temperature thenconcentrated. The residue was purified by preparative LCMS (pH=10method; XBridge™ preparative C18 5 μm OBD™ column) to give the titleproduct (20 mg, 29%). LCMS calc. for C₂₅H₂₈N₇O₂ (M+H)⁺: m/z=458.2.Found: 458.1. ¹H NMR (DMSO-d₆): δ 10.81 (s, 1H); 9.50 (s, 1H); 8.60 (d,1H); 8.42 (s, 1H); 8.30 (d, 1H); 8.20 (d, 1H); 8.18 (s, 1H); 8.10 (d,1H); 8.00 (d, 1H); 7.20 (s, 1H); 5.35 (s, 1H); 3.90 (s, 3H); 3.20-3.30(m, 3H); 2.85 (t, 1H); 2.65 (t, 1H); 2.55 (t, 1H); 2.30 (m, 1H); 1.65(br, 2H); 0.95 (s, 3H) ppm.

Example 44N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)quinoline-2-carboxamide

The title compound was prepared using procedures similar to that ofExample 43 (yield: 25%). LCMS calc. for C₂₆H₃₀N₇O₂ (M+H)⁺: m/z=472.1.Found: 472.1. ¹H NMR (DMSO-d₆): δ 10.81 (s, 1H); 9.50 (s, 1H); 8.60 (d,1H); 8.42 (s, 1H); 8.30 (d, 1H); 8.20 (d, 1H); 8.18 (s, 1H); 8.10 (d,1H); 8.00 (d, 1H); 7.20 (s, 1H); 5.35 (s, 1H); 4.20 (q, 2H); 3.20-3.30(m, 3H); 2.85 (t, 1H); 2.65 (t, 1H); 2.55 (t, 1H); 2.30 (m, 1H); 1.65(br, 2H); 1.45 (t, 3H); 0.95 (s, 3H) ppm.

Example 45N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)quinoline-2-carboxamide

In a microwave tube, a mixture of tert-butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[7-(6-methoxypyridin-3-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(100 mg, 15 mmol), (6-methoxypyridin-3-yl)boronic acid (29 mg, 0.19mmol), and DIPEA (0.078 mL, 0.45 mmol) in 1,4-dioxane (4.1 mL) and water(0.40 mL) was purged with N₂ for 5 min. beforebis(tri-t-butylphosphine)palladium (20 mg, 0.04 mmol) was added. Thereaction mixture was then heated at 110° C. for 1 h. The crude mixturewas diluted with EtOAc and washed with saturated NaHCO₃ solution andbrine, dried over Na₂SO₄, and concentrated. The residue was purified bysilica gel column chromatography (40 g column, eluting with 0-100% EtOAcin hexanes) to give the coupling product. LCMS (M+H): 699.2.

The above coupling product was dissolved in small amount of MeOH and 4 NHCl was added and the resulting mixture was stirred at room temperaturefor 1 h. The solvent was removed and a few drops aq. NH₄Cl was added.The resulting mixture was purified by preparative LCMS (pH=10 method;XBridge™ preparative C18 5 m OBD™ column) to give the title product.LCMS calc. for C₂₇H₂₉N₆O₃ (M+H)⁺: m/z=485.2. Found: 485.1. ¹H NMR(DMSO-d₆): δ 10.75 (br, 1H); 9.50 (s, 1H); 8.80 (s, 1H); 8.70 (d. 1H);8.40 (s, 1H); 8.30 (m, 2H); 8.22 (d, 1H); 8.15 (d, 1H); 7.20 (s, 1H);7.00 (d, 1H); 5.15 (s, 1H); 3.95 (s, 3H); 3.20 (m, 2H); 2.85 (t, 1H);2.60 (t, 1H); 2.50 (t, 1H); 2.25 (m, 1H); 0.95 (d, 3H) ppm.

Example 46N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)quinoline-2-carboxamide

The title compound was prepared using procedures similar to that ofExample 45. LCMS calc. for C₃₀H₃₄N₇O₃ (M+H)⁺: m/z=540.3. Found: 540.1.¹H NMR (DMSO-d₆): δ 10.65 (br, 1H); 9.50 (s, 1H); 8.75 (s, 1H); 8.65 (d,1H); 8.35 (s, 1H); 8.25 (m, 2H); 8.20 (m, 2H); 8.15 (d, 1H); 7.15 (d,1H); 6.95 (d, 1H); 5.10 (d, 1H); 3.75 (m, 4H); 3.10-3.30 (m, 3H); 2.85(t, 1H); 2.65 (m, 2H); 2.25 (m, 1H); 1.70 (br, 2H); 0.95 (d, 3H) ppm.

Example 47N-(4-((3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(pyridin-3-yl)quinoline-2-carboxamide

The title compound was prepared using a method analogous to that ofExample 45. LCMS calc. for C₂₆H₂₇N₆O₂ (M+H)⁺: m/z=455.2. Found: 455.2.

Example 48N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide

Step 1.tert-Butyl[(3S,5R)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

A mixture of tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.60g, 2.0 mmol), 7-bromoquinoline-2-carboxylic acid (0.50 g, 2.0 mmol),DIPEA (0.70 mL, 4.0 mmol), and 0.5 g molecular sieves in1,2-dichloroethane (30 mL) was stirred at room temperature for 0.5 h.HATU (0.031 g, 0.082 mmol) was added. The resulting mixture was stirredat room temperature overnight, diluted with EtOAc (50 mL), filteredthrough a diatomaceous earth funnel, washed with saturated NaHCO₃, waterand brine, and then dried over Na₂SO₄. After concentrating under reducedpressure, the residue was purified with 40 g silica gel column using aCombiFlash® apparatus eluting with EtOAc/hexanes (10-100%) to give theproduct as brown solid (0.95 g, 90%). LCMS calc. for C₂₆H₃₁BrN₅O₃(M+H)⁺: m/z=540.2. Found: 540.2.

Step 2.N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide

In a microwave tube, a mixture of tert-butyl[(3S,5R)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(80 mg, 0.15 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (24 mg, 0.19mmol), and DIPEA (0.078 mL, 0.45 mmol) in 1,4-dioxane (4.1 mL) and water(0.40 mL) was purged with N₂ for 5 min. beforebis(tri-t-butylphosphine)palladium (20 mg, 0.04 mmol) was added. Thereaction mixture was heated at 110° C. for 1 h. The crude mixture wasdiluted with EtOAc and washed with saturated NaHCO₃ solution and brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (40 g column eluting with 0-100% EtOAc inhexanes) to give a Suzuki coupling product. LCMS calc. for C₃₀H₃₆N₇O₃(M+H)⁺: m/z=542.3. Found: 542.2.

The Suzuki coupling product was dissolved in a small amount of MeOH and4 N HCl was added. The resulting mixture was stirred at room temperaturefor 1 h, then concentrated under reduced pressure, and treated with afew drops aq. NH₄Cl. The product was purified by preparative LCMS (pH=10method; XBridge™ preparative C18 5 μm OBD™ column) to give the titleproduct (25%). LCMS calc. for C₂₅H₂₈N₇O (M+H)⁺: m/z=442.2. Found: 442.1.¹H NMR (DMSO-d₆): δ 10.55 (br, 1H); 9.45 (s, 1H); 8.60 (d, 1H); 8.35 (s,1H); 8.30 (d, 1H); 8.20 (m, 2H); 8.15 (d, 1H); 8.10 (s, 1H); 8.00 (d,1H); 7.20 (d, 1H); 3.95 (s, 3H); 3.20-3.40 (m, 3H); 2.30 (t, 2H); 2.20(m, 1H); 2.10 (dd, 1H); 1.70 (br, 1H); 0.90 (m, 4H) ppm.

Example 49N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)quinoline-2-carboxamide

The title compound was prepared using a method analogous to that ofExample 48 (30% yield). LCMS calc. for C₂₈H₂₇N₆O (M+H)⁺: m/z=463.2.Found: 463.1. ¹H NMR (DMSO-d₆): δ 10.55 (br, 1H); 9.45 (s, 1H); 8.80 (d,1H); 8.40 (d. 1H); 8.35 (d, 1H); 8.30 (d, 1H); 8.10 (d, 1H); 8.00 (d,1H); 7.90 (t, 1H); 7.85 (d, 1H); 7.70 (t, 1H); 7.15 (d, 1H); 3.20-3.30(m, 3H); 2.30 (m, 2H); 2.15 (m, 1H); 2.00 (dd, 1H); 1.50 (br, 1H); 0.85(m, 4H) ppm.

Example 50

N-(4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(4-hydroxypiperidin-1-yl)quinoline-2-carboxamide

The title compound was prepared using a method analogous to that ofExample 28. LCMS calc. for C₂₆H₃₃N₆O₂ (M+H)⁺: m/z=461.3. Found: 461.2.

Example 51N-{4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)-1,5-naphthyridine-2-carboxamide

Step 1. Benzyl(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidine-1-carboxylate

To a round bottom flask containingcis-3-(Boc-amino)-5-(trifluoromethyl)piperidine (Molbridge, 10.0 g, 37.3mmol) and NaHCO₃ (18.8 g, 224 mmol) was added THF (200 mL), followed bywater (200 mL). To the above mixture, benzyl chloroformate (20.1 g, 112mmol) was added dropwise over a period of 30 min via syringe pump. Themixture was stirred at room temperature for 2 h. The reaction wasdiluted with EtOAc and water. The organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The resultingresidue was purified on silica gel (340 g, 15% EtOAc in hexanes) to giveas a white foamy solid which was subjected to chiral HPLC separation(Phenomenex Lux Cellulose C-1, 5 μm, 21.2×250 mm column, eluting with15% EtOH in hexanes, at flow rate of 18 mL/min, with a loading of 100 mgin 1000 μL at 220 nm wavelength) to give the sub-title compound(retention time: 9.1 min) as a white foamy solid (6.51 g, 43%). LCMScalculated for C₁₉H₂₅F₃N₂NaO₄ (M+Na)⁺: m/z=425.2; found 425.2.

Step 2. tert-Butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate

To a solution of benzyl(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidine-1-carboxylate(4.71 g, 11.7 mmol) in MeOH (70.0 mL) was added 10 wt % Pd on carbon(1.886 g). The reaction was purged with H₂ and stirred under H₂atmosphere (balloon pressure) for 3 h. The reaction mixture was filteredthrough a pad of celite (eluted with MeOH). The filtrate wasconcentrated in vacuo to give the sub-title product as a white solid(3.04 g, 97%) which was used directly in the next step without furtherpurification.

Step 3: tert-Butyl[(3S,5R)-1-(3-nitropyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitropyridine (580 mg, 3.6 mmol), tert-butyl[(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (800 mg, 3 mmol),IPA (5.0 mL) and DIPEA (1.0 mL, 6.0 mmol) was stirred at 80° C.overnight. The reaction mixture was concentrated under reduced pressureand the residue was purified by column chromatography on silica gelusing CombiFlash® apparatus eluting with EtOAc/hexane (50-100%). Thepurification gave 1.0 g (80% yield) of the sub-title compound as ayellow solid. LCMS calc. for C₁₆H₂₂F₃N₄O₄ (M+H)⁺: m/z=: 391.2; found:391.1.

Step 4: tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

A mixture of tert-butyl[(3S,5R)-1-(3-nitropyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(1 g, 2 mmol), iron powder (0.57 g, 10 mmol), AcOH (16 mL) and water (2mL) was stirred at room temperature for 60 min. When the reaction wascomplete, the mixture was allowed to cool, concentrated under reducedpressure and diluted with EtOAc. The resulting mixture was filteredthrough a diatomaceous earth pad. The filtrate was concentrated underreduced pressure, and the residue was dissolved in 1 M NaOH aqueoussolution and extracted with EtOAc (100 mL, 3×). The combined organiclayers were washed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 0.9 g (100% yield) of thesub-title compound as a brown solid. LCMS calc. for C₁₆H₂₄F₃N₄O₂ (M+H)⁺:m/z=: 361.2; found: 361.1.

Step 5. tert-Butyl[(3S,5R)-1-(3-{[(7-Bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

A mixture of 7-bromo-1,5-naphthyridine-2-carboxylic acid (632 mg, 2.50mmol), tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(900 mg, 2.50 mmol), HATU (1.71 g, 4.50 mmol) and DIPEA (1.30 mL, 7.49mmol) in DMF (6 mL) was stirred at RT for 2 h. The reaction was quenchedwith brine, extracted with EtOAc (2×). The combined organic phases werewashed with water, brine and dried over Na₂SO₄, and then concentrated.The residue was purified by Combi-Flash eluted with EtOAc/hexanes(0-100%) to give the sub-title product as off-white solid (1.03 g, 69%).LCMS calc. for C25H₂₇BrF₃N₆O₃ (M+H)⁺: m/z=: 595.1; found: 595.0.

Step 6N-{4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)-1,5-naphthyridine-2-carboxamide

In a sealed tube a mixture of (2-cyanophenyl)boronic acid (12 mg, 0.079mmol), and tert-butyl[(3S,5R)-1-(3-{[(7-bromo-1,5-naphthyridin-2-yl)carbonyl]amino}pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(30 mg, 0.61 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was purgedwith N₂ for 5 min before bis(tri-t-butylphosphine)palladium (3 mg, 0.1mmol) was added. The reaction mixture was then heated on the benchtop at110° C. for 1 h. The mixture was concentrated, and the resulting residuewas purified by silica gel column chromatography eluting withEtOAc/hexanes (0-100%) to give tert-butyl[(3S,5R)-1-[3-({[7-(2-cyanophenyl)-1,5-naphthyridin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate.The above made Suzuki product was treated with DCM (1 mL) and TFA (1 mL)at RT for 1 h. The mixture was concentrated. The residue was purified byprep. LC/MS (PH=10) to yield the title product as white powder. LCMScalc. for C₂₇H₂₃F₃N₇O (M+H)⁺: m/z=: 518.2; found: 518.2.

Example 52.N-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]quinoline-2-carboxamide

In a sealed tube a mixture of tert-butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(50 mg, 0.07 mmol), [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]boronicacid (21 mg, 0.095 mmol), and DIPEA (0.039 mL, 0.22 mmol) in 1,4-dioxane(2.0 mL) and water (0.2 mL) was purged with N₂ for 5 min beforebis(tri-t-butylphosphine)palladium (10 mg, 0.02 mmol) was added. Thereaction mixture was then heated on the bench top at 110° C. for 1 h.The crude was purified by silica gel column chromatography eluted withEtOAc/hexanes (40 g column, 0-100% EtOAc in hexanes), to give tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-{3-[({7-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]quinolin-2-yl}carbonyl)amino]pyridin-4-yl}piperidin-3-yl)carbamate.The above made Suzuki product was dissolved in MeOH, and 4 N HCl wasadded and the resulting mixture was stirred for 1 h at r.t. The reactionmixture was concentrated and treated with aq. NH₄OH and then purifiedwith pH 10 prep-LCMS to give the title product. LCMS calc. forC₃₁H₃₅N₆O₄ (M+H)⁺: m/z: 555.3; found: 555.1.

Example A. Pim Enzyme Assays

Pim-1 and Pim-3 kinase assays-20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μL compound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM mgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 μM Biotin-labeled BAD peptide substrate (AnaSpec 62269),1 mM ATP, and 2.5 pM (Pim-1, Invitrogen PV3503) or 1.25 pM (Pim-3,Millipore 14-738) enzyme for 1 h at 25° C. Reactions were stopped byaddition of 10 μL STOP Buffer (150 mM Tris, pH=7.5, 150 mM NaCl, 75 mMEDTA, 0.01% Tween-20, 0.3% BSA), supplemented with Phospho-Bad (Ser112)Antibody (Cell Signaling 9291) diluted 666-fold, and Streptavidin donorbeads (PerkinElmer 6760002) along with Protein-A acceptor beads(PerkinElmer 6760137) at 15 μg/mL each. Supplementation of the STOPbuffer with beads and stopping the reactions were done under reducedlight. Prior to the stopping reactions STOP buffer with beads waspreincubated for 1 h in the dark at room temperature. After stopping thereactions, plates were incubated for 1 h in the dark at room temperaturebefore reading on a PHERAstar FS plate reader (BMG Labtech) underreduced light.

Pim-2 kinase assay-20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μL compound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM mgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 μM Fluorescein-labeled CREBtide peptide substrate(Invitrogen PV3508), 1 mM ATP, and 1 nM enzyme (Invitrogen PV3649) for 2h at 25° C. Reactions were stopped by addition of 10 μL TR-FRET DilutionBuffer (Invitrogen PV3574) with 30 mM EDTA and 1.5 nM LanthaScreenTb-CREB pSer133 antibody (Invitrogen PV3566). After 30 min. incubationat room temperature, plates were read on a PHERAstar FS plate reader(BMG Labtech).

Compounds of the invention having an IC₅₀ of 2 μM or less when testedfor PIM kinase activity under the assay conditions disclosed above areconsidered active.

Although the above in vitro assays are conducted at 1 mM ATP compoundscan also be evaluated for potency and in vitro activity against PIMtargets utilizing K_(m) conditions, where the concentration of ATP isset to the K_(m) value and the assay is more sensitive to PIM inhibitionactivity.

Example B. Pim Cellular Assays

One or more compounds of the invention were tested for inhibitoryactivity of PIM according to at least one of the following cellularassays. Compounds of the invention having an IC₅₀ of 10 μM or less whentested for PIM kinase activity under the cellular assay conditionsdisclosed below would be and were considered active.

Pim Cell Proliferation Assay

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS. 12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI, 10% FBS and IMDM 20% FBS(Mediatech, Manassas, Va.) respectively. To measure theanti-proliferation activity of test compounds, both cell lines areplated with the culture medium (2×10³ cells/well/in 200 μL) into 96-wellpolystyrene ultralow binding (Costar), in the presence or absence of aconcentration range of test compounds. After 4 days, [³H]-thymidine, 1μCi/10 μL/well (PerkinElmer, Boston, Mass.) in culture medium is thenadded to the cell culture for an additional 16 h before the incorporatedradioactivity is separated by filtration with a Packard Micro plateHarvester with water through a 0.3% PEI pre wetted GF/B filter plates(Packard Bioscience/PerkinElmer, Boston, Mass.). The plate is measuredby liquid scintillation counting with a TopCount (PerkinElmer). IC₅₀determination is performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

Pim Cell Proliferation Assay

MOLM-16 cells are purchased from DSMZ (Germany) and maintained in theculture medium recommended, RPMI, 20% FBS. To measure theanti-proliferation activity of test compounds, the cells are plated withthe RPMI, 10% FBS (1×10⁴ cells/well/in 200 μL) into 96-well polystyreneultralow binding plates (Costar) in the presence or absence of aconcentration range of test compounds. After 4 days, [³H]-thymidine, 1μCi/10 μL/well (PerkinElmer, Boston, Mass.) in RPMI, 10% FBS is thenadded to the cell culture for an additional 16 h before the incorporatedradioactivity is separated by filtration with a Packard Micro plateHarvester with water through a 0.3% PEI pre wetted GF/B filter plates(Packard Bioscience/PerkinElmer, Boston, Mass.). The plate is measuredby liquid scintillation counting with a TopCount (PerkinElmer). IC₅₀determination is performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

Pim pBAD Signaling Assays

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS. 12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI, 10% FBS and IMDM 20% FBS(Mediatech, Manassas, Va.) respectively. To measure the pBAD inhibitoryactivity of the compounds, both cell lines are plated with the culturemedium (1×10⁶/well/100 μL for KG1A and 4×10⁵ cells/well/in 100 μL forKMS12BM) into 96-well V bottom polypropylene plates (Matrix, ThermoFisher, USA) and incubated 30 min. at 37° C. to normalize cell signalingfrom handling. Test compounds are added at an appropriate concentrationrange and further incubated for 2.5 h for KMS.12.BM cells and 4 h forKG1-A cells. Plates are centrifuged at 2000 RPM for 10 min. andsupernatants aspirated. 100 μL lysis buffer with protease inhibitors(Cell Signaling Technologies, Danver, Mass., Sigma, St Louis Mo., EMD,USA) is added to the pellets, mixed well and set on ice for 30 min.Lysates are frozen overnight at −80° C. To measure the pBAD activity, aCell Signaling ELISA kit (Cell Signaling Path Scan phosphor pBAD ELISA)is utilized. 50 μL of the lysate is tested per the ELISA protocol andthe data analysis is performed by software on a SpectrMax5 plate reader(Molecular Devices, Sunnyvale, Calif.). IC₅₀ determination is performedby fitting the curve of percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 5.0 software.

Data obtained for the Example compounds, obtained using the methodsdescribed in Example A, are provided in Table 1.

TABLE 1 Exam- PIM1 PIM2 PIM3 KMS.12.BM pBAD ple IC₅₀ (nM)^(a) IC₅₀(nM)^(b) IC₅₀ (nM)^(a) IC₅₀ (nM)^(c) 1 * + * # 2 * + * # 3 * ++ * #4 * + * # 5 * ++ * # 6 * + * # 7 * + * # 8 * ++ * # 9 * ++ * # 10 * + *# 11 * ++ * ## 12 * + * # 13 * + * # 14 * + * ## 15 * ++ * ## 16 * + * #17 * ++ * ## 18 * ++ * ## 19 * ++ * ### 20 * + * ## 21 * ++ * ##22 * + * # 23 * + * # 24 * + * # 25 * + * # 26 * + * ## 27 * ++ * ##28 * ++ * 29 * ++ * 30 * + * ## 31 * ++ * ## 32 * ++ * 33 * +++ *34 * + * ## 35 * + * # 36 * + * # 37 * + * # 38 * + * # 39 * + * ## 40 *++ * 41 ** +++ ** ## 42 * ++ * ## 43 * + * # 44 * + * # 45 * + * #46 * + * # 47 * + * # 48 * + * # 49 * + * # 50 * + * # 51 * + * #52 * + * ## ^(a)IC₅₀ ≦ 10 nM: *; 10 nM < IC₅₀ ≦ 50 nM: **; 50 nM < IC₅₀≦ 500 nM: ***; 500 nM < IC₅₀ ≦ 2000 nM: ****. ^(b)IC₅₀ ≦ 100 nM: +; 100nM < IC₅₀ ≦ 1000 nM: ++; 1000 nM < IC₅₀ ≦ 10000 nM: +++. ^(c)IC₅₀ ≦ 50nM: #; 50 nM < IC₅₀ ≦ 250 nM: ##; 250 nM < IC₅₀ ≦ 2000 nM: ###; 2000 nM< IC₅₀ ≦ 10000 nM: ####.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

1-81. (canceled)
 82. A method of treating cancer comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of any one of the following Formulae(III) to (VIII):

or a pharmaceutically acceptable salt thereof, wherein: R³ is C₁₋₆alkyl, Cy, or -L-Cy; L is unsubstituted C₁₋₆ alkylene or C₁₋₆ alkylenesubstituted with 1, 2 or 3 substituents independently selected from F,Cl, CN, OH and O(C₁₋₆ alkyl); Cy is unsubstituted or substituted C₆₋₁₀aryl, unsubstituted or substituted 5-10 membered heteroaryl,unsubstituted or substituted C₃₋₆ cycloalkyl or unsubstituted orsubstituted 4-11 membered heterocycloalkyl, wherein the substitutedC₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₆ cycloalkyl or 4-11 memberedheterocycloalkyl forming Cy is substituted with 1, 2, or 3 substituentseach independently selected from halogen, R^(Cy1), C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl,C₁₋₆ haloalkyl, CN, OH, and C₁₋₆ alkoxy; wherein each R^(Cy1) is,independently, C₁₋₆ alkyl, each of which is independently unsubstitutedor substituted with 1, 2 or 3 substituents independently selected fromhalogen, CN, and OR^(a1); and wherein R^(a1) is independently, at eachoccurrence, selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.83. The method of claim 82, wherein the cancer is a cancer wherein theexpression or activity of at least one of Pim1, Pim2 and Pim3 isupregulated.
 84. The method of claim 82, wherein the cancer is a cancerwherein an oncogene is activated.
 85. The method of claim 82, whereinthe cancer is a cancer wherein Myc or Bcl2 is activated.
 86. The methodof claim 82, wherein the cancer is a solid tumor or a hematologicalcancer.
 87. The method of claim 82, wherein the cancer is prostatecancer, colon cancer, esophageal cancer, endometrial cancer, ovariancancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer,gastric cancer, breast cancer, lung cancer, cancer of the head or neck,thyroid cancer, glioblastoma, sarcoma, bladder cancer, lymphoma,leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, diffuselarge-B cell lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma,Hodgkin lymphoma or multiple myeloma.
 88. A method of treating anmyeloproliferative disorder, comprising administering to a patient inneed of such treatment a therapeutically effective amount of a compoundof claim 82, or a pharmaceutically acceptable salt thereof.
 89. Themethod of claim 88, wherein the myeloproliferative disorder ispolycythemia vera, essential thrombocythemia, chronic myelogenousleukemia, myelofibrosis, primary myelofibrosis, myelofibrosis withmyeloid metaplasia, post polycythemia vera/essential thrombocythemiamyelofibrosis, post-essential thrombocythemia myelofibrosis or postpolycythemia vera myelofibrosis. 90-93. (canceled)
 94. A method ofreducing angiogenesis or tumor metastasis, comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of claim 82, or a pharmaceutically acceptable salt thereof.95. The method of claim 82 wherein R³ is C₁₋₆ alkyl.
 96. The method ofclaim 82 wherein R³ is Cy.
 97. The method of claim 82 wherein R³ is-L-Cy.
 98. The method of claim 96 wherein Cy is unsubstituted orsubstituted C₆₋₁₀ aryl.
 99. The method of claim 98 wherein Cy isunsubstituted phenyl or substituted phenyl.
 100. The method of claim 99wherein Cy is phenyl substituted with 1, 2, or 3 substituentsindependently selected from halogen, CN, and OR^(a1).
 101. The method ofclaim 96 wherein Cy is unsubstituted or substituted 5-10 memberedheteroaryl.
 102. The method of claim 101 wherein Cy is unsubstituted orsubstituted pyridinyl or pyrazolyl.
 103. The method of claim 102 whereinCy is pyridinyl substituted with 1 substituent selected from C₆₋₁₀ aryl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-7 memberedheterocycloalkyl, OH, and C₁₋₆ alkoxy.
 104. The method of claim 103wherein Cy is 6-(morpholin-4-yl)pyridin-3-yl or 6-methoxypyridin-3-yl.105. The method of claim 102 wherein Cy is pyrazolyl substituted with aC₁₋₆ alkyl group.
 106. The method of claim 105 wherein Cy is1-methyl-1H-pyrazol-4-yl or 1-ethyl-1H-pyrazol-4-yl.
 107. The method ofclaim 96 wherein Cy is unsubstituted or substituted C₃₋₆ cycloalkyl.108. The method of claim 96 wherein Cy is unsubstituted or substituted4-11 membered heterocycloalkyl.
 109. The method of claim 108 wherein Cyis unsubstituted or substituted heterocycloalkyl, the ring atoms ofwhich consist of carbon atoms and 1, 2, or 3 heteroatoms independentlyselected from N and O.
 110. The method of claim 108 wherein a nitrogenatom of Cy forms the bond between Cy and the remainder of the molecule.111. The method of claim 109 wherein Cy is unsubstituted or substitutedpyrrolidinyl, piperidinyl, azetidinyl, piperazinyl or oxopiperazinyl.112. The method of claim 111 wherein Cy is unsubstituted pyrrolidin-1-ylor is pyrrolidin-1-yl substituted with a C₁₋₆ haloalkyl group.
 113. Themethod of claim 111 wherein Cy is unsubstituted piperidin-1-yl orpiperidin-1-yl substituted at the 4-position.
 114. The method of claim113 wherein Cy is substituted piperidin-1-yl substituted by 1substituent selected from R^(Cy2), CN, and OR^(a).
 115. The method ofclaim 114 wherein Cy is 4-hydroxypiperidin-1-yl, 4-cyanopiperidin-1-yl,4-methoxypiperidin-1-yl, 4-(pyridin-4-yl)piperidin-1-yl, or4-(morpholin-4-yl)piperidin-1-yl.
 116. The method of claim 111 whereinCy is unsubstituted azetidin-1-yl or azetidin-1-yl substituted with twoC₁₋₆ alkyl groups.
 117. The method of claim 111 wherein Cy isunsubstituted or substituted piperazin-1-yl.
 118. The method of claim117 wherein Cy is 4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl. 119.The method of claim 111 wherein Cy is unsubstituted or substituted3-oxopiperazin-1-yl.
 120. The method of claim 119 wherein Cy is4-methyl-3-oxopiperazin-1-yl or 4-ethyl-3-oxopiperazin-1-yl.
 121. Themethod of claim 109 wherein Cy is unsubstituted or substituted3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, ormorpholinyl.
 122. The method of claim 109 wherein Cy is unsubstituted orsubstituted heterocycloalkyl, the ring atoms of which consist of carbonatoms and 1 oxygen atom.
 123. The method of claim 82 wherein L isunsubstituted C₁₋₆ alkylene.
 124. The method of claim 123 wherein L isCH₂.
 125. The method of claim 82 wherein each R^(Cy1) is methyl orethyl.
 126. The method of claim 82 wherein Cy is substituted with a 4 to7 membered heterocycloalkyl.
 127. The method of claim 82 wherein R^(a1)is selected from H and C₁₋₆ alkyl.
 128. A method of treating cancercomprising administering to a patient in need of such treatment atherapeutically effective amount of a compound selected from thefollowing compounds:N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluorophenyl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-isopropyl-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-(tetrahydro-2H-pyran-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropenyl-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-morpholin-4-yl-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-azetidin-1-ylquinoline-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)quinoline-2-carboxamide;N-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)quinoline-2-carboxamide;N-(4-(3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(pyridin-3-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)quinoline-2-carboxamide;N-(4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(4-hydroxypiperidin-1-yl)quinoline-2-carboxamide;N-{4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)-1,5-naphthyridine-2-carboxamide;andN-{4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]quinoline-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 129. A method of treatingcancer comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound selected from thefollowing compounds:N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-(2,6-difluorophenyl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropyl-1,5-naphthyridine-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropenyl-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-yl-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-ethylquinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-isopropylquinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-cyanopiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-pyridin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-ethyl-3-oxopiperazin-1-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-methoxypiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[3-(trifluoromethyl)pyrrolidin-1-yl]quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-pyrrolidin-1-ylquinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(3,3-dimethylazetidin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-azetidin-1-ylquinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl}-7-(2,6-difluoro-4-methoxyphenyl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl)}-7-(6-methoxypyridin-3-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl)}-7-(6-morpholin-4-ylpyridin-3-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl)}-7-(1-ethyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl)}-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl)}-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl)}-7-(4-cyanopiperidin-1-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-5-cyclopropyl-4-hydroxypiperidin-1-yl]pyridin-3-yl)}-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-1,5-naphthyridine-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl)}-7-(-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-ethyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-methoxypyridin-3-yl)quinoline-2-carboxamide;N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(6-morpholin-4-ylpyridin-3-yl)quinoline-2-carboxamide;N-(4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(pyridin-3-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)quinoline-2-carboxamide;N-(4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-7-(4-hydroxypiperidin-1-yl)quinoline-2-carboxamide;N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}-7-(2-cyanophenyl)-1,5-naphthyridine-2-carboxamide;and N-{4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]quinoline-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 130. A method of treatingcancer comprising administering to a patient in need of such treatment atherapeutically effective amount of the compoundN-{4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}-7-morpholin-4-ylquinoline-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 131. The method of claim82, wherein the cancer is a solid tumor.
 132. The method of claim 82,wherein the cancer is prostate cancer, colon cancer, esophageal cancer,endometrial cancer, ovarian cancer, uterine cancer, renal cancer,hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lungcancer, cancer of the head or neck, thyroid cancer, glioblastoma,sarcoma, or bladder cancer.
 133. The method of claim 82, wherein thecancer is a hematological cancer.
 134. The method of claim 82, whereinthe cancer is lymphoma, leukemia, acute lymphoblastic leukemia, acutemyelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenousleukemia, diffuse large-B cell lymphoma, mantle cell lymphoma,non-Hodgkin lymphoma, Hodgkin lymphoma or multiple myeloma.